Thienopyridine derivatives, their production and use

ABSTRACT

The present invention provides thienopyridine derivatives, which are useful as anti-inflammatory drugs, particularly as remedies for arthritis; processes for producing them, and pharmaceutical compositions containing them. The thienopyridine derivatives are represented by the formula (I):                    
     wherein G is a halogen atom, hydroxyl group, an optionally substituted amino group, etc.; alk is an optionally substituted lower alkylene group; X is O, S, —(CH 2 ) q —, etc.; R is an optionally substituted amino group, etc.; ring B is an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y is O, S, a group of                    
     (wherein Ra, Rb and Rc are the same or different and, each is H, a halogen atom, an optionally substituted hydrocarbon group, etc.), etc.; and ring A may be substituted.

This application is the National Phase filing of International PatentApplication No. PCT/JP01/01483, filed Feb. 28, 2001.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel thienopyridine derivatives orsalts thereof, which have anti-inflammatory activity, bone resorptionsuppressive activity, immune cytokine production suppressive activity,etc., and are useful as medicaments such as anti-arthritis drugs, etc.,and to their production and use.

PRIOR ART

Arthritis is an inflammatory disease of joints, which includes, as majordiseases, rheumatoid arthritis and related diseases with inflammationobserved in joints.

Among them, rheumatoid arthritis, also called chronic rheumatoidarthritis, is a chronic polyarthritis that is characterized byinflammatory changes in the synovia in the internal capsules of jointsas the major lesion. Arthritis such as rheumatoid arthritis is aprogressive disease, which brings about joint dysfunctions such as jointdeformity, arthrokleisis, and the like, and often leads to seriousdisability if it is exacerbated without being treated effectively.

Heretofore, drugs available for treating these arthritides have beensteroids such as corticosteroids (e.g., cortisone, etc.), non-steroidalanti-inflammatory drugs (e.g., aspirin, piroxicam, indomethacin, etc.),gold compounds (e.g., aurothiomalate, etc.), antirheumatic drugs (e.g.,chloroquine preparation, D-penicillamine, etc.), gout suppressants(e.g., colchicines, etc.), immunosuppressants (e.g., cyclophosphamide,azathioprine, methotrexate, levamisole, etc.) and the like. However,some of these drugs have been problematic such as serious adversereactions, adverse reactions precluding a long-term administration,insufficient efficacy, lack of effect on established arthritis or thelike.

Thienopyridine derivatives or thienodipyridine derivatives have beenreported as anti-inflammatory drugs, especially as remedies forarthritis, in JP 8-225577 A (PCT International Application PublicationNo. WO96/14319); JP 10-36374 A (PCT International ApplicationPublication No. WO97/40050), and PCT International ApplicationPublication No. WO97/65916 and the like.

OBJECTS OF THE INVENTION

Medicaments with superior prophylactic and therapeutic efficacy againstarthritis and the like have been still desired for the clinicaltreatment of arthritis and the like.

SUMMARY OF THE INVENTION

Under these circumstances, the present inventors have studiedintensively and, as a result, the present inventors have found thatnovel thienopyridine derivatives, which are represented by the followingformula (I) and are characteristic in ring B and group G in the3-position, are useful as suppressants of joint destruction bypossessing potent anti-inflammatory activity, in particularantiarthritic activity, are useful as bone resorption suppressants bypossessing the excellent bone resorption suppressing activity withdirect effect on the bone, and further are useful as immunosuppressants.The present inventors have further studied based on these findings. Thusthe present invention has been completed.

That is, the present invention relates to:

(1) A compound represented by the formula (I):

wherein G represents a halogen atom, hydroxyl group, an optionallysubstituted amino group, an optionally substituted lower alkyl group oran optionally substituted alkoxy group; alk represents an optionallysubstituted lower alkylene group; X represents oxygen atom, anoptionally oxidized sulfur atom, or —(CH₂)_(q)— (q represents an integerof 0 to 5); R represents an optionally substituted amino group or anoptionally substituted heterocyclic group; ring B represents anoptionally substituted Y-containing 5- to 8-membered ring whose ringconstituent atoms contain no nitrogen atom; Y represents oxygen atom, anoptionally oxidized sulfur atom,

(wherein Ra and Rb are the same or different and, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring; and Rcrepresents hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group); and ring Arepresents an optionally substituted benzene ring, or a salt thereof;

(2) The compound according to the above (1), wherein alk is methylene;

(3) The compound according to the above (1), wherein G is a halogenatom;

(4) The compound according to the above (1), wherein G is chlorine atom;

(5) The compound according to the above (1), wherein X is —(CH₂)_(q)— (qrepresents an integer of 0 to 5);

(6) The compound according to the above (1), wherein X is a bond;

(7) The compound according to the above (1), wherein the optionallysubstituted amino group represented by R is —N(R¹) (R²) (wherein R¹ andR², which may be the same or different, respectively, represent hydrogenatom, an optionally substituted hydrocarbon group, or an optionallysubstituted acyl, sulfonyl, sulfinyl, or heterocyclic group, or R¹ andR² may be combined each other to form an optionally substitutednitrogen-containing 5- to 7-membered heterocyclic group);

(8) The compound according to the above (7), wherein R¹ and R² arecombined each other to form a nitrogen-containing optionally substituted5- to 7-membered heterocyclic group;

(9) The compound according to the above (7), wherein R¹ and R² are acylgroups;

(10) The compound according to the above (1), wherein R is an optionallysubstituted nitrogen-containing heterocyclic group;

(11) The compound according to the above (1), wherein the substituent onthe optionally substituted heterocyclic group represented by R is oxogroup;

(12) The compound according to the above (1), wherein R is

wherein ring C represents a 5- to 7-membered heterocyclic groupoptionally containing one or more hetero atoms selected from nitrogen,sulfur and oxygen atoms, in addition to the nitrogen atom;

(13) The compound according to the above (1), wherein ring B is anoptionally substituted 6-membered ring containing Y;

(14) The compound according to the above (1), wherein the substituentson ring B are one to four substituents selected from a C₁₋₆ alkyl groupand a halogen atom;

(15) The compound according to the above (1), wherein ring B is a ringrepresented by the formula:

wherein Y′ and Y″ represent carbon atom, sulfur atom or oxygen atom,respectively; n represents an integer of 0 to 4; and Y is as defined inthe above 1, which may be substituted with one to four substituentsselected from a C₁₋₆ alkyl group and a halogen atom;

(16) The compound according to the above (1), wherein Y is an optionallyoxidized sulfur atom or

(17) The compound according to the above (1), wherein ring A is benzenering which may be substituted with one to four substituents selectedfrom a halogen atom, nitro group, an optionally substituted alkyl group,an optionally substituted hydroxyl, an optionally substituted thiolgroup, an optionally substituted amino group, an optionally substitutedacyl group, an optionally esterified carboxyl group, and an optionallysubstituted aromatic ring group;

(18) The compound according to the above (1), wherein the substituent onring A is a C₁₋₆ alkoxy group or hydroxyl group;

(19) The compound according to the above (1), wherein the compoundrepresented by formula (I) is:

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methly}-2,5-pyrrolidinedioneethylene ketal;

3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dioneor an optically active substance thereof or a salt thereof;

3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dioneor an optically active substance thereof or a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor an optically active substance thereof or a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a saltthereof;

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dioneor a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof; or

2-aminomethyl-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3:4,5]thieno[2,3-b]pyridineor an optically active substance thereof or a salt thereof;

(20) The compound according to the above (1), wherein the compoundrepresented by formula (I) is:

3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dioneor an optically active substance thereof or a salt thereof;

3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dioneor an optically active substance thereof or a salt thereof; or

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor an optically active substance thereof or a salt thereof;

(21) The compound according to the above (1), wherein the compoundrepresented by formula (I) is:

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dioneor a salt thereof; or

1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

(22) The compound according to the above (1), wherein the compoundrepresented by formula (I) is:

1-{[3-chloro-4-(4-hydroxyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;

4-{3-chloro-2-[2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyl}diisobutyl phosphate or a salt thereof; or

butyl4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyl carbonate or a salt thereof;

(23) A prodrug of the compound according to the above (1);

(24) A process for producing a compound represented by the generalformula (I):

wherein G represents a halogen atom, hydroxyl group, an optionallysubstituted amino group, an optionally substituted lower alkyl group oran optionally substituted alkoxy group; alk represents an optionallysubstituted lower alkylene group; X represents oxygen atom, anoptionally oxidized sulfur atom, or —(CH₂)_(q)— (q represents an integerof 0 to 5); R represents an optionally substituted amino group or anoptionally substituted heterocyclic group; ring B represents anoptionally substituted Y-containing 5- to 8-membered ring whose ringconstituent atoms contain no nitrogen atom; Y represents oxygen atom, anoptionally oxidized sulfur atom,

(wherein Ra and Rb are the same or different and, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring; and Rcrepresents hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group); and ring Arepresents an optionally substituted benzene ring, or a salt thereofwhich comprises reacting a compound represented by the formula (II-1):

wherein Q represents a leaving group; and the other symbols are asdefined above, or a salt thereof, with a compound represented by theformula (III):

R—X¹H  (III)

wherein R is as defined above; and X¹ represents oxygen atom, or anoptionally oxidized sulfur atom, or a salt thereof to obtain a compoundrepresented by the formula (I-1):

wherein each symbol is as defined above, or a salt thereof; or

reacting a compound represented by the formula (II-2):

wherein each symbol is as defined above, or a salt thereof, with acompound represented by the formula (IV):

wherein R¹ and R², which may be the same or different, respectively,represent an optionally substituted hydrocarbon group, an optionallysubstituted acyl group, an optionally substituted sulfonyl group, or anoptionally substituted heterocyclic group, or R¹ and R² may be combinedeach other to form an optionally substituted nitrogen-containing 5- to7-membered ring, or a salt thereof to obtain a compound represented bythe formula (I-2):

wherein each symbol is as defined above, or a salt thereof; or

subjecting a compound represented by the formula (I-3):

wherein ring B¹ represents an optionally substituted Y¹-containing 5- to8-membered ring whose ring constituent atoms contain no nitrogen atom;Y¹ represents sulfur atom or

and the other symbols are as defined above, or a salt thereof tooxidation to obtain a compound represented by the formula (I-4):

wherein ring B² represents an optionally substituted Y²-containing 5- to8-membered ring whose ring constituent atoms contain no nitrogen atom;Y² represents an oxidized sulfur atom or

and the other symbols are as defined above, or a salt thereof; or

reacting a compound represented by the formula (II-3):

wherein G′ represents a halogen atom; and the other symbols are asdefined above, or a salt thereof, with

(C₆H₅)₃P

in a solvent to obtain a compound represented by formula (VI):

wherein each symbol is as defined above, then reacting the compoundrepresented by the formula (VI) with a compound represented by theformula (VII):

Z¹—(CH₂)_(q′)CHO  (VII)

wherein Z¹ represents an optionally substituted heterocyclic group; andq′ represents an integer of 0 to 4, or a salt thereof to obtain acompound represented by formula (VIII):

wherein each symbol is as defined above, or a salt thereof, and furthersubjecting the compound represented by formula (VIII) or a salt thereofto reduction to obtain a compound represented by the formula (I-5):

wherein each symbol is as defined above, or a salt thereof; or

reacting a compound represented by the formula (II-1):

wherein each symbol is as defined above, or a salt thereof, with acompound represented by formula (XII):

R—H  (XII)

wherein R is as defined above, or a salt thereof to obtain a compoundrepresented by the formula (I-9):

wherein each symbols is as defined above, or a salt thereof;

(25) A pharmaceutical composition comprising a compound represented bythe general formula (I):

wherein G represents a halogen atom, hydroxyl group, an optionallysubstituted amino group, an optionally substituted lower alkyl group oran optionally substituted alkoxy group; alk represents an optionallysubstituted lower alkylene group; X represents oxygen atom, anoptionally oxidized sulfur atom, or —(CH₂)_(q)— (q represents an integerof 0 to 5); R represents an optionally substituted amino group or anoptionally substituted heterocyclic group; ring B represents anoptionally substituted Y-containing 5- to 8-membered ring whose ringconstituent atoms contain no nitrogen atom; Y represents oxygen atom, anoptionally oxidized sulfur atom,

(wherein Ra and Rb are the same or different and, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring; and Rcrepresents hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group); and ring Arepresents an optionally substituted benzene ring, a prodrug thereof, ora pharmaceutically acceptable salt thereof;

(26) The pharmaceutical composition according to the above (25) forprevention or treatment of inflammatory diseases;

(27) The pharmaceutical composition according to the above (25) forprevention or treatment of arthritis;

(28) The pharmaceutical composition according to the above (25) forprevention or treatment of rheumatism;

(29) The pharmaceutical composition according to the above (25) forprevention or treatment of chronic rheumatoid arthritis;

(30) The pharmaceutical composition according to the above (25), whichis a bone resorption suppressant;

(31) The pharmaceutical composition according to the above (25) forprevention or treatment of osteoporosis;

(32) The pharmaceutical composition according to the above (25), whichis a suppressant of cytokine production;

(33) The pharmaceutical composition according to the above (25) forprevention or treatment of autoimmune diseases;

(34) The pharmaceutical composition according to the above (25) forprevention or treatment of rejection reaction after organtransplantation;

(35) The pharmaceutical composition according to the above (25), whichis a T-cell differentiation-controlling medicament.

(36) A method for preventing or treating inflammatory diseases whichcomprises administering an effective amount of a compound represented bythe formula (I):

wherein G represents a halogen atom, hydroxyl group, an optionallysubstituted amino group, an optionally substituted lower alkyl group oran optionally substituted alkoxy group; alk represents an optionallysubstituted lower alkylene group; X represents oxygen atom, anoptionally oxidized sulfur atom, or —(CH₂)_(q)— (q represents an integerof 0 to 5); R represents an optionally substituted amino group or anoptionally substituted heterocyclic group; ring B represents anoptionally substituted Y-containing 5- to 8-membered ring whose ringconstituent atoms contain no nitrogen atom; Y represents oxygen atom, anoptionally oxidized sulfur atom,

(wherein Ra and Rb are the same or different and, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring; and Rcrepresents hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group); and ring Arepresents an optionally substituted benzene ring, a prodrug thereof, ora pharmaceutically acceptable salt thereof, to a mammal in need of theprevention or treatment; and

(37) Use of a compound represented by the formula

wherein G represents a halogen atom, hydroxyl group, an optionallysubstituted amino group, an optionally substituted lower alkyl group oran optionally substituted alkoxy group; alk represents an optionallysubstituted lower alkylene group; X represents oxygen atom, anoptionally oxidized sulfur atom, or —(CH₂)_(q)— (q represents an integerof 0 to 5); R represents an optionally substituted amino group or anoptionally substituted heterocyclic group; ring B represents anoptionally substituted Y-containing 5- to 8-membered ring whose ringconstituent atoms contain no nitrogen atom; Y represents oxygen atom, anoptionally oxidized sulfur atom,

(wherein Ra and Rb are the same or different and, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring; and Rcrepresents hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group); and ring Arepresents an optionally substituted benzene ring, a prodrug thereof, ora pharmaceutically acceptable salt thereof in the manufacture of apharmaceutical composition for preventing or treating inflammatorydiseases.

DETAILED EXPLANATION OF THE INVENTION

The explanation of all definitions included in the above-mentionedgeneral formulas and in the scope of the present invention as well aspreferred examples thereof will be described below.

In the above formula (I), G represents a halogen atom (e.g., chlorine,bromine, iodine or fluorine); hydroxyl group, an optionally substitutedamino group [e.g., amino group, a N—(C₁₋₆ alkyl)amino group such asmethylamino, ethylamino, propylamino, butylamino, etc.; a N,N-di(C₁₋₆alkyl)amino group such as dimethylamino, diethylamino, dipropylamino,dibutylamino, etc.]; an optionally substituted lower alkyl group [e.g.,a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.) which maybe substituted with one to three halogen atoms]; or an optionallysubstituted lower alkoxy group [e.g., a C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy, propoxy, butoxy, etc.) which may be substituted with 1to 3 halogen atoms]. A preferred example of G is a halogen atom withchlorine being more preferred.

In the above formula, G′ represents a halogen atom (e.g., chlorine,bromine, iodine or fluorine). A preferred example of G′ is chlorine.

Examples of the lower alkylene group of the optionally substituted loweralkylene group represented by alk include a C₁₋₆ alkylene group such asmethylene, ethylene, propylene, and the like.

Examples of the substituents of the lower alkylene group represented byalk include 1 to 4 substituents selected from a halogen atom (e.g.,chlorine, bromine, iodine or fluorine), hydroxyl group, an optionallysubstituted amino group [e.g., amino group, a N—(C₁₋₆ alkyl)amino groupsuch as methylamino, ethylamino, propylamino, butylamino, etc.; aN,N-di(C₁₋₆ alkyl)amino group such as dimethylamino, diethylamino,dipropylamino, dibutylamino, etc.], a optionally substituted lower alkylgroup [e.g., a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl,etc.) which may be substituted with 1 to 3 halogen atom, etc.], and anoptionally substituted alkoxy group [e.g., a C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy, propoxy, butoxy, etc.) which may be substituted 1 to 3halogen atom, etc.].

In the above formula (I), X represents oxygen atom, an optionallyoxidized sulfur atom, or —(CH₂)_(q)— (q represents an integer of 0 to 5,preferably an integer of 0 to 3, and more preferably 0). As theoptionally oxidized sulfur atom represented by X, there is thio group,sulfinyl group, and sulfonyl group, with thio group being preferred.

Preferably, X is —(CH₂)_(q)— (q represents an integer of 0 to 5,preferably an integer of 0 to 3, and more preferably 0).

In the above formula (I), examples of the optionally substituted aminogroup represented by R include a group represented by the formula:—N(R¹) (R²) (wherein R¹ and R², which may be the same or different,respectively, represent hydrogen atom or a hydrocarbon group, an acylgroup, sulfonyl group, sulfinyl group or a heterocyclic group(preferably an acyl group), which respectively may be substituted, or R¹and R²are combined each other to form an optionally substitutednitrogen-containing heterocyclic ring), and the like.

Examples of the hydrocarbon group in the optionally substitutedhydrocarbon group represented by R¹ or R² include an aliphatichydrocarbon group, an alicyclic hydrocarbon group, analicyclic-aliphatic hydrocarbon group, an aromatic aliphatic hydrocarbongroup, an aromatic hydrocarbon group, and the like.

Examples of said aliphatic hydrocarbon group include a C₁₋₈ saturatedaliphatic hydrocarbon group (e.g., C₁₋₈ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl,etc.), a C₂₋₈ unsaturated aliphatic hydrocarbon group (e.g., C₂₋₈alkenyl, C₂₋₈ alkynyl, C₄₋₈ alkadienyl, and C₄₋₈ alkadiynyl, such asvinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl,1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 3-hexynyl, 2,4-hexadlynyl, 5-hexynyl, 1-heptynyl, 1-octynyl,etc.), and the like.

Examples of said alicyclic hydrocarbon group include C₃₋₇ saturatedalicyclic hydrocarbon group (e.g., C₃₋₇ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and C₅₋₇unsaturated alicyclic hydrocarbon group (e.g., C₅₋₇ cycloalkenyl andC₅₋₇ cycloalkadienyl such as 1-cyclopentenyl, 2-cyclopentenyl,3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl,etc.) and the like.

Examples of said alicyclic-aliphatic hydrocarbon group include, amongthe residues formed by combination of the above-mentioned alicyclichydrocarbon groups and the above-mentioned aliphatic hydrocarbon groups,that having 4 to 9 carbon atoms such as cycloalkylalkyl,cycloalkylalkeny, and the like, each of which having 4 to 9 carbon atoms(e.g., cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl,cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl,cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cyclobutylethyl,etc.).

Examples of said aromatic alicyclic hydrocarbon group include C₇₋₉phenylalkyl (e.g., benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl,2-phenylpropyl, 1-phenylpropyl, etc.) and C₁₁₋₁₃ naphthylalkyl (e.g.,α-naphthylmethyl, αnaphthylethyl, β-naphthylmethyl, β-naphthylethyl,etc.) and the like.

Examples of said aromatic hydrocarbon group include phenyl, naphthyl(α-naphthyl and β-naphthyl), and the like.

As for the hydrocarbon group in the optionally substituted hydrocarbongroup represented by R¹ or R², C₁₋₆, straight chain or branched chainalkyl, particularly C₁₋₄, straight chain alkyl or C₃₋₄, branched chainalkyl is preferred. Specifically, groups such as methyl, ethyl, propyl,isopropyl, butyl, and the like are preferred.

Examples of the acyl group in the optionally substituted acyl grouprepresented by R¹ or R² include (i) formyl, or (ii) groups where thecarbonyl group is combined to a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenylgroup, a C₂₋₁₀ alkynyl group, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, or anaromatic group (e.g., phenyl group, pyridyl group, etc.), (e.g., acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).

Examples of the sulfonyl group in the optionally substituted sulfonylgroup represented by R¹ or R² include groups where the sulfonyl group iscombined to a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀ alkynylgroup, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, or an aromatic group (e.g.,phenyl group, pyridyl group, etc.), (e.g., methanesulfonyl,ethanesulfonyl, benzenesulfonyl, etc.).

Examples of the sulfinyl group in the optionally substituted sulfinylgroup represented by R¹ or R² include groups where the sulfinyl group iscombined to a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀ alkynylgroup, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, or an aromatic group (e.g.,phenyl group, pyridyl group, etc.), (e.g., methanesulfinyl,ethanesulfinyl, benzenesulfinyl, etc.).

Examples of the heterocyclic group in the optionally substitutedheterocyclic group represented by R¹ or R² include (i) 5- to 7-memberedheterocyclic groups containing one sulfur atom, one nitrogen atom, orone oxygen atom, (ii) 5- to 6-membered heterocyclic groups containing2-4 nitrogen atoms, (iii) 5- to 6-membered heterocyclic groupscontaining 1-2 nitrogen atoms and one sulfur or oxygen atom, or thelike, and (iv) these heterocyclic groups may be condensed with a 5- to6-membered ring containing 2 or less nitrogen atoms, benzene ring, or a5-membered ring containing one sulfur atom. In addition, each of theheterocyclic groups exemplified in (i) to (iv) may be a saturated orunsaturated heterocyclic group and the unsaturated heterocyclic groupmay be either aromatic or non-aromatic.

Examples of the heterocyclic group in the optionally substitutedheterocyclic group represented by R¹ and R² include anaromatic-monocyclic heterocyclic group, an aromatic condensedheterocyclic group, and a non-aromatic, heterocyclic group.

Specific examples of the heterocyclic group in the optionallysubstituted heterocyclic group represented by R¹ and R² include (i) anaromatic-monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl,oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, etc.), (ii) an aromatic condensedheterocyclic group (e.g., benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl,benzooxazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.),and (iii) a non-aromatic, heterocyclic group (e.g., oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,piperazinyl, etc.).

In the case where R¹ and R² are combined each other to form a ring,particularly a nitrogen-containing 5- to 7-membered ring, examples ofsuch —N(R¹) (R²) include 1-pyrrolyl, 1-pyrrolidinyl, 1-imidazolidinyl,1-pyrazolidinyl, 1-piperidyl (piperidino), 1-piperazinyl, 4-morpholinyl(morpholino), 4-thiomorpholinyl, homopiperazin-1-yl, pyrazol-1-yl,imidazol-1-yl, 1,3-thiadiazol-3-yl, 1,3-oxadiazol-3-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1,2,4-triazol-4-yl,1,2,3-triazol-1-yl, 1,2,4-triazol-2-yl, tetrazol-1-yl, oxazol-3-yl,thiazol-3-yl, and a partly or whole saturated nitrogen-containingheterocyclic group thereof. These heterocyclic groups may have the 1 to3 same substituents as those of the hydrocarbon group, the acyl group,the sulfonyl group, the sulfinyl group and the heterocyclic group asdescribed hereinafter, and may be condensed with the above-mentionedaromatic, monocyclic heterocyclic group or an aromatic ring such asbenzene ring or the like. Specific examples in the case where theheterocyclic group condensed with the aromatic ring includebenzimidazol-1-yl, indol-1-yl, 1H-indazol-1-yl, and the like;preferably, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, imidazol-1-yl,morpholino (4-morpholinyl), piperidino (1-piperidyl), oxazolidin-3-yl,thiazolidin-3-yl, hydantoin-1-yl, pyrrolidino (1-pyrrolidin-1-yl) andthe like, each of which may be substituted and may be condensed withbenzene ring; more preferably, a nitrogen-containing 5- to 7-memberedring that may have 1 to 2 oxo groups (e.g., 2,4-dioxooxazolidin-3-yl,2,4-dioxothiazolidin-3-yl, 2,5-dioxohydantoin-1-yl,2,5-dioxopyrrolidin-1-yl, etc.), with 2,5-dioxopyrrolidin-1-yl beingparticularly preferred.

The hydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² may have 1 to 3substituents at any possible positions on the chain or the ring thereof.

Examples of such a substituent of the hydrocarbon group, the acyl group,the sulfonyl group, the sulfinyl group and the heterocyclic grouprepresented by R¹ or R² include an aliphatic-chain hydrocarbon group, analicyclic hydrocarbon group, an aryl group, an aromatic, heterocyclicgroup, a non-aromatic, heterocyclic group, a halogen atom, an optionallysubstituted amino group, amidino group, an optionally substituted acylgroup, an optionally substituted hydroxyl group, an optionallysubstituted thiol group, an optionally esterified or amidated carboxylgroup, an aralkyl group (e.g., a C₆₋₁₄ aryl-C₁₋₆ alkyl group, etc.), acarbamoyl group, an optionally substituted thocarbamoyl group, anN-mono-substituted carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl, phenylcarbamoyl, etc.), an N,N-disubstituted carbamoylgroup (N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, piperidinocarbamoul,morpholinocarbamoyl, etc.), a sulfamoyl group, an N-mono-substitutedsulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl,p-toluenesulfamoyl, etc.), an N,N-disubstituted sulfamoyl group (e.g.,N,N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl,morpholinosulfamoyl, etc.), mercapto group, sulfo group, cyano group,azido group, nitro group, nitroso group, oxo group, and the like.

Examples of the aliphatic-chain hydrocarbon group as the substituent ofthe hydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² include astraight or branched chain aliphatic hydrocarbon group such as an alkylgroup (preferably, a C₁₋₁₀ alkyl group), an alkenyl group (preferably, aC₂₋₁₀ alkenyl group), an alkynyl group (preferably, a C₂₋₁₀ alkynylgroup), and the like. Preferred examples of said alkyl group includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl,hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl, andthe like. Preferred examples of said alkenyl group include vinyl, allyl,isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like. Preferredexamples of said alkynyl group include ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, andthe like.

Examples of the alicyclic hydrocarbon group as the substituent of thehydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² include asaturated or unsaturated C₃₋₈ alicyclic hydrocarbon group such as a C₃₋₈cycloalkyl group, a C₃₋₈ cycloalkenyl group, a C₄₋₈ cycloalkadienylgroup and the like. Preferred examples of said C₃₋₈ cycloalkyl groupinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, and the like. Preferred examples of said C₃₋₈cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, and the like. Preferred examplesof said C₄₋₈ cycloalkadienyl group include 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like.

The aryl group as the substituent of the hydrocarbon group, the acylgroup, the sulfonyl group, the sulfinyl group and the heterocyclic grouprepresented by R¹ or R², and the aryl group in the aralkyl group mean amonocyclic, or condensed polycyclic aromatic hydrocarbon group.Preferred examples thereof include phenyl, naphthyl, anthryl,phenanthryl, acenaphthenyl, and the like, with C₆₋₁₀ aryl such asphenyl, 1-naphthyl, 2-naphthyl, and the like being more preferred.

Examples of an optionally substituted thiocarbamoyl group as thesubstituent of the hydrocarbon group, the acyl group, the sulfonylgroup, the sulfinyl group and the heterocyclic group represented by R¹or R² include methylthiocarbamoyl, ethylthiocarbamoyl,phenylthiocarbamoyl and the like.

Preferred examples of the aromatic heterocyclic group as the substituentof the hydrocarbon group, the acyl group, the sulfonyl group, thesulfinyl group and the heterocyclic group represented by R¹ or R²include an aromatic monocyclic heterocyclic group (e.g., a 5- to6-memberd aromatic, monocyclic heterocyclic group containing 1 to 4heteroatoms selected from nitrogen, sulfur, and oxygen atoms, such asfuryl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pirazinyl, triazinyl, etc.) as wellas an aromatic condensed heterocyclic group (e.g., a 8- to 12-memberdaromatic, monocyclic heterocyclic group containing 1 to 4 heteroatomsselected from nitrogen, sulfur, and oxygen atoms, such as benzofuranyl,isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,benzoimidazolyl, benzooxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl,phenanthrolinyl, indolizinyl, pyrrolo [1,2-b]pyridazinyl,pyrazo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.),and the like.

Preferred examples of the non-aromatic heterocyclic group as thesubstituent of the hydrocarbon group, the acyl group, the sulfonylgroup, the sulfinyl group and the heterocyclic group represented by R¹or R² include a 5- to 8-membered non-aromatic, monocyclic heterocyclicgroup containing 1 to 4 heteroatoms selected from nitrogen, sulfur, andoxygen atoms, such as oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and thelike.

Examples of the halogen atom as the substituent of the hydrocarbongroup, the acyl group, the sulfonyl group, the sulfinyl group and theheterocyclic group represented by R¹ or R² include fluorine, chlorine,bromine, and iodine, with fluorine and chlorine being particularlypreferred.

Examples of the optionally substituted amino group as the substituent ofthe hydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² include aminogroup, an N-mono-substituted amino group, and N,N-disubstituted aminogroup. Examples of said substituted amino groups include an amino grouphaving one or two C₁₋₁₀ alkyl groups, C₃₋₇ cycloalkyl groups, C₂₋₁₀alkenyl groups, C₂₋₁₀ alkynyl groups C₃₋₇ cycloalkenyl groups, C₆₋₁₄aryl groups that may have a C₁₋₄ alkyl group, a heterocyclic group(e.g., the same heterocyclic group as that as the substituent of thehydrocarbon group, the acyl group, the sulfonyl group, and theheterocyclic group represented by R¹ or R²), or C₁₋₁₀ acyl groups (e.g.C₃₋₇ alkanoyl, etc.) as the substituents thereof (e.g., methylamino,dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino,cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino,propionylamino, benzoylamino, nicotinoylamino, etc.). In addition, thetwo groups in said substituted amino group may be combined to form anitrogen-containing, 5- to 7-membered ring (e.g., the same ring as thatformed by combining R¹ and R² each other, preferably, piperidine,morpholino, thiomorpholino, etc.).

Further, the carbamoyl group and the sulfamoyl group as the substituentof the hydrocarbon group, the acyl group, the sulfonyl group, thesulfinyl group and the heterocyclic group represented by R¹ or R² mayhave the same one or two substituents as those of the above-mentionedsubstituted amino group.

Examples of the optionally substituted acyl group as the substituent ofthe hydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² include (i)formyl or (ii) a group where the carbonyl group is combined with a C₁₋₁₀alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀ alkynyl group, a C₃₋₇cycloalkyl group, a C₅₋₇ cycloalkenyl group, or an aromatic group (e.g.,phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl,isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, etc.) and the like.

Examples of the optionally substituted hydroxyl group as the substituentof the hydrocarbon group, the acyl group, the sulfonyl group, thesulfinyl group and the heterocyclic group represented by R¹ or R²include hydroxyl group and a hydroxyl group having an appropriatesubstituent, particularly, that to be used as a protective group (e.g.,alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.).

As the preferred alkoxy, there is C₁₋₁₀ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy,etc.), C₃₋₇ cycloalkyloxy (e.g., cyclobutoxy, cyclopentyloxy,cyclohexyloxy, etc.).

As the preferred alkenyloxy, there is C₂₋₁₀ alkenyloxy (e.g., allyloxy,crotyloxy, 2-pentenyloxy, 3-hexenyloxy, etc.) or C₃₋₇ cycloalkyloxy(e.g., 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.).

As the preferred alkynyloxy, there is C₂₋₁₀ alkynyloxy (e.g.,ethynyloxy, 2-propinyloxy, etc.).

As the preferred aralkyloxy, there is, for example, phenyl-C₁₋₄ alkyloxy(e.g., benzyloxy, phenethyloxy, etc.).

As the preferred acyloxy, there is C₂₋₄ alkanoyloxy (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, etc.), C₃₋₄ alkenoyloxy, orC₃₋₄ alkynoyloxy.

As the preferred aryloxy, there is phenoxy, a phenoxy optionallysubstituted with a halogen atom such as 4-chlorophenoxy, or the like.

Examples of the optionally substituted thiol group as the substituent ofthe hydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² include thiolgroup and a thiol group having an appropriate substituent, particularly,that to be used as a protective group (e.g., alklythio, alkenylthio,alkynylthio, aralkylthio, acylthio, arylthio, etc.), and examples ofsaid substituent include the same substituent as that of the optionallysubstituted hydroxyl group.

Examples of the optionally esterified carboxyl group as the substituentof the hydrocarbon group, the acyl group, the sulfonyl group, thesulfinyl group and the heterocyclic group represented by R¹ or R²include, in addition to carboxyl group, an alkyloxycarbonyl group, analkenyloxycarbonyl, an alkynyloxycarbonyl, an aralkyloxycarbonyl group,an acyoxycarbonyl group, an aryloxycarbonyl group, and the like.

Examples of the alkyl group in said alkyloxycarbonyl group include aC₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, etc.).

Examples of the alkenyl group in said alkenyloxycarbonyl group include aC₂₋₆ alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-propenyl,1-butenyl, 2-butenyl, 3-methylallyl, etc.).

Examples of the alkynyl group in said alkynyloxycarbonyl group include aC₂₋₆ alkynyl group (e.g., ethynyl, 2-propynyl, etc.).

The aralkyl group in said aralkyloxycarbonyl group means an aryl-alkylgroup (e.g., C₆₋₁₀ aryl-C₁₋₆ alkyl, etc.). The aryl group in saidaryl-alkyl group means a monocyclic or condensed polycyclic aromatichydrocarbon group, and preferred examples include phenyl, naphthyl,anthryl, phenanthryl, acenaphthenyl, and the like. They may have asubstituent such as a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀alkynyl group, a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyl group, aC₄₋₈ cycloalkadienyl group, an aryl group (e.g., C₆₋₁₄ aryl, etc.), anaromatic heterocyclic group (e.g., the same aromatic heterocyclic groupas that of the substituent of the hydrocarbon group, the acyl group, thesulfonyl group, the sulfinyl group and the heterocyclic grouprepresented by R¹ or R², etc.), a non-aromatic heterocyclic group (e.g.,the same non-aromatic heterocyclic group as that of the substituent ofthe hydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R², etc.), anaralkyl group (e.g., a C₆₋₁₄ aryl-C₁₋₆ alkyl group, etc.), amino group,an N-mono-substituted amino group (e.g., the same N-mono-substitutedamino group as that of the substituent of the hydrocarbon group, theacyl group, the sulfonyl group, the sulfinyl group and the heterocyclicgroup represented by R¹ or R², preferably a N-mono-C₁₋₄ alkylaminogroup, etc.), a N,N-disubstituted amino group (e.g., the sameN,N-disubstituted amino group as that of the substituent in thehydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R², preferably aN,N-di-C₁₋₄ alkylamino group, etc.), amidino group, an acyl group (e.g.,the same acyl group as that of the substituent of the hydrocarbon group,the acyl group, the sulfonyl group, the sulfinyl group and theheterocyclic group represented by R¹ or R², etc.), carbamoyl group, aN-mono-substituted carbamoyl group (e.g., a N-mono-C₁₋₄ alkylcarbamoylgroup such as methylcarbamoyl, ethylcarbamoyl, etc.; phenylcarbamoyl;etc.), a N,N-disubstituted carbamoyl group (a N,N-di-C₁₋₄ alkylcarbamoylgroup such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.;piperidinocarbamoyl; morpholinocarbamoyl; etc.), sulfamoyl group, aN-mono-substituted sulfamoyl group (e.g., a N-mono-C₁₋₄ alkylsulfamoylgroup such as methylsulfamoyl, ethylsulfamoyl, etc.; phenylsulfamoyl;p-toluenesulfamoyl; etc.), a N,N-disubstituted sulfamoyl group (e.g., aN,N-disubstituted C₁₋₄ alkylsulfamoyl group such asN,N-dimethylsulfamoyl, etc.; a N-C₁₋₄ alkyl-N-phenylsulfamoyl group suchas N-methyl-N-phenylsulfamoyl, etc.; piperidinosulfamoyl;morpholinosulfamoyl; etc.), carboxyl group, a C₁₋₁₀ alkoxycarbonyl group(e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.),hydroxyl group, a C₁₋₁₀ alkoxy group, a C₂₋₁₀ alkenyloxy group, a C₃₋₇cycloalkyloxy group, an aralkyloxy group (e.g., C₆₋₁₄ aryl-C₁₋₆alkyloxy, etc.), an aryloxy group (e.g., C₆₋₁₄ aryloxy, etc.), mercaptogroup, a C₁₋₁₀ alkylthio group, an aralkylthio group (e.g., C₆₋₁₄aryl-C₁₋₆ alkylthio, etc.), an arylthio group (e.g., C₆₋₁₄ arythio,etc.), sulfo group, cyano group, azido group, nitro group, nitrosogroup, a halogen atom, or the like. As for an alkyl group in saidaryl-alkyl group, a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,butyl, etc.) is preferred. Preferred examples of said aralkyl group,i.e., an aryl-alkyl group include benzyl, phenethyl, 3-phenylpropyl,(1-naphthyl)methyl, (2-naphthyl)methyl, and the like. Among them,benzyl, phenethyl, and the like are preferred.

As the acyl group in said acyloxycarbonyl group, for example, there areformyl, a C₂₋₄ alkanoyl group, a C₃₋₄ alkenoyl group, a C₃₋₄ alkynoylgroup, and the like.

As the aryl group in said aryloxycarbonyl group, for example, there arephenyl, naphthyl, and the like.

Examples of the amidated carboxyl group as the substituent of thehydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group represented by R¹ or R² include thecarboxyl group amidated with an optionally substituted amino group asthe substituent of the hydrocarbon group, the acyl group, the sulfonylgroup, and the heterocyclic group represented by the above mentioned R¹or R², each of which may be substituted.

In the above-mentioned formula (I), examples of the heterocyclic groupof the optionally substituted heterocyclic group represented by Rinclude the same heterocyclic group as that defined with respect to theabove-mentioned R¹ or R². The optionally substituted heterocyclic grouprepresented by R may be attached to the adjacent X through any possibleatom (e.g., nitrogen, carbon) in the heterocyclic group. It is preferredthat the optionally substituted heterocyclic group represented by R isattached to X through nitrogen atom.

Examples of the heterocyclic group of the optionally substitutedheterocyclic group represented by R (preferably, a nitrogen-containingheterocyclic group) include (i) a 5- to 7-membered heterocyclic groupcontaining one sulfur atom, one nitrogen atom, or one oxygen atom, (ii)a 5- to 7-membered heterocyclic group containing 2 to 4 nitrogen atoms,or (iii) a 5- to 7-membered heterocyclic group containing 1 to 2nitrogen atoms and one sulfur atom or one oxygen atom, or (iv) theseheterocyclic groups may be condensed with a 5- to 6-membered ringcontaining 2 or less nitrogen atoms, benzene ring, or a 5-membered ringcontaining one sulfur atom. Each of the heterocyclic groups exemplifiedin (i) to (iv) may be a saturated or unsaturated heterocyclic group, andthe unsaturated heterocyclic group may be either aromatic ornon-aromatic.

These heterocyclic groups may have 1 to 3 substituents at any possiblepositions. Examples of such a substituent include the same substituentas that defined with respect to the substituent of the hydrocarbongroup, the acyl group, the sulfonyl group, the sulfinyl group and theheterocyclic group represented by R¹ or R² (preferably, oxo group), orthe like.

Specific examples of the optionally substituted heterocyclic grouprepresented by R, in the case where the constituent carbon atom in theheterocyclic group is attached to the adjacent X, include 2-imidazolyl,1,2,4-triazol-3-yl, 2-thiazolyl, 2-oxazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-benzoimidazolyl, and the like.

Examples of the optionally substituted heterocyclic group represented byR, in the case where the constituent nitrogen atom in the heterocyclicgroup is attached to the adjacent X, include 1-pyrrolyl, 1-pyrrolidinyl,1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidyl (piperidino),1-piperazinyl, 4-morpholinyl (morpholino), 4-thiomorpholinyl,homopiperazin-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,3-thiadiazol-3-yl,1,3-oxadiazol-3-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl,1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,tetrazol-1-yl, oxazol-3-yl, thiazol-3-yl, and partly or whole saturated,nitrogen-containing, heterocyclic groups thereof. These heterocyclicgroups may have the 1 to 3 same substituent as the optional substituentof the hydrocarbon group, the acyl group, the sulfonyl group, thesulfinyl group and the heterocyclic group represented by R¹ and R², andmay be condensed with the above-mentioned non-aromatic, monocyclicheterocyclic group or aromatic ring such as benzene ring or the like.Specific examples, in the case where the heterocyclic group is condensedwith an aromatic ring, include benzimidazol-1-yl, indol-1-yl,1H-indazol-1-yl, and the like; preferably, 1,2,4-triazol-1-yl,1,2,4-triazol-2-yl, imidazol-1-yl, morpholino (4-morpholinyl),piperidino (1-piperidyl), oxazolidin-3-yl, thiazolidin-3-yl,hydantoin-1-yl, pyrrolidino (1-pyrrolidin-1-yl), and the like, each ofwhich may be substituted and may be condensed with benzene ring; morepreferably, a nitrogen-containing, 5- to 7-membered ring that may have 1to 2 oxo groups (e.g., 2,4-dioxooxazolidin-3-yl,2,4-dioxothiazolidin-3-yl, 2,5-dioxohydantoin-1-yl,2,5-dioxopyrrolidin-1-yl, etc.), with 2,5-dioxopyrrolidin-1-yl beingparticularly preferred.

R is preferably

wherein ring C₁ represents a 5- to 7- membered heterocyclic group whichmay contain 1 to 3 hetero atoms selected from nitrogen, sulfur andoxygen in addition to the nitrogen atom, and may be substituted with the1 to 3 same substituents of the hydrocarbon group, the acyl group, thesulfonyl group, the sulfinyl group and the heterocyclic grouprepresented by R¹ and R².

More preferably, R is

wherein ring C represents a 5- to 7-membered heterocyclic group whichmay contain one or more (1 to 3, preferably 1) hetero atoms selectedfrom nitrogen, sulfur and oxygen, in addition to the nitrogen atom.

In the above formula (I), Y is oxygen atom, an optionally oxidizedsulfur atom, or

(wherein Ra and Rb, which may be the same or different, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring; and Rcrepresents hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group).

Examples of the optionally substituted hydrocarbon group represented byRa, Rb, or Rc include the same group as the optionally substitutedhydrocarbon group represented by the above-mentioned R¹ or R². Amongthem, methyl, ethyl, isopropyl, propyl, butyl, benzyl, phenethyl, 2-,3-, or 4-pyridylmethyl, or the like is preferred as the optionallysubstituted hydrocarbon group represented by Ra, Rb, or Rc.

Examples of the optionally substituted acyl group represented by Ra, Rb,or Rc include the same group as the optionally substituted acyl grouprepresented by the above-mentioned R¹ or R². In particular, benzoyl,acetyl or the like is preferred.

Examples of the optionally substituted carbamoyl group represented byRa, Rb, or Rc include the same group as the optionally substitutedcarbamoyl group defined with respect to the substituent of thehydrocarbon group, acyl group, sulfonyl group, or heterocyclic grouprepresented by the above-mentioned R¹ or R².

Examples of the optionally substituted thiocarbamoyl group representedby Ra, Rb, or Rc include the same group as the optionally substitutedthiocarbamoyl group defined with respect to the substituent of theoptionally substituted hydrocarbon group, acyl group, sulfonyl group, orheterocyclic group represented by the above-mentioned R¹ or R².

Examples of the optionally substituted sulfonyl group represented by Ra,Rb, or Rc include the same group as the optionally substituted sulfonylgroup represented by the above-mentioned R¹ or R².

Examples of the optionally substituted sulfinyl group represented by Ra,Rb, or Rc include the same group as the optionally substituted sulfinylgroup represented by the above-mentioned R¹ or R².

Examples of the optionally substituted hydroxyl group represented by Ra,Rb, or Rc include the same group as the optionally substituted hydroxylgroup defined with respect to the substituent of the hydrocarbon group,acyl group, sulfonyl group, the sulfinyl group or heterocyclic grouprepresented by the above-mentioned R¹ or R².

Examples of the optionally substituted thiol group represented by Ra,Rb, or Rc include the same group as the optionally substituted thiolgroup defined with respect to the substituent of the hydrocarbon group,acyl group, sulfonyl group, the sulfinyl group or heterocyclic grouprepresented by the above-mentioned R¹ or R².

Examples of the optionally substituted, esterified carboxyl grouprepresented by Ra, Rb, or Rc include the same group as the optionallysubstituted, esterified carboxyl group defined with respect to thesubstituent of the hydrocarbon group, the acyl group, the sulfonylgroup, the sulfinyl group or the heterocyclic group represented by theabove-mentioned R¹ or R².

Examples of the optionally substituted heterocyclic group represented byRa, Rb, or Rc include the same group as the optionally substitutedheterocyclic group defined with respect to the above-mentioned R¹ or R².

Also, examples of the 5- to 7-membered ring, in the case where Ra and Rbare combined each other to form the 5- to 7-membered ring, include aC₃₋₇ saturated hydrocarbon ring (e.g., cyclopentane, cyclohexane, andcycloheptane) or a 5- to 7-membered, saturated heterocyclic groupcontaining one to four heteroatoms selected from nitrogen, sulfur, andoxygen [e.g., nitrogen-containing, C₃₋₇ saturated hydrocarbon ring(e.g., tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine),oxygen-containing, C₅₋₇ saturated hydrocarbon (e.g., dioxolan, dioxane,dioxepane ring), etc.], preferably a C₅₋₇ saturated hydrocarbon ring(e.g., cyclopentane, cyclohexane, cycloheptane) or an oxygen-containing,C₅₋₇ saturated hydrocarbon ring (e.g., dioxolan, dioxane, dioxepanering), or the like.

Preferred examples of Rc include hydrogen atom, hydroxyl group, methoxygroup, ethoxy group, and the like.

Preferred examples of Y include an optionally substituted sulfur atom,or

In the above-mentioned formula (I), when ring B represents to form aY-containing optionally substituted 5- to 8-membered (preferably6-membered) ring whose ring constituent atoms contain no nitrogen atomtogether with the carbon-double bond portion in the adjacent thiophenering. Also, ring B may form a Y-containing lactone ring in the casewhere Y is

As the 5- to 8-membered ring in the Y-containing optionally substituted5- to 8-membered ring whose ring constituent atoms contain no nitrogenatom, for example, there is:

wherein Ra, Rb, and Rc are as defined above; n is an integer of 0 to 4;and k is an integer of 0 to 4 (where the sum of n and k is 1 to 4);preferably, n and k represent 1, or the like as well as a ring a part orthe whole of which is converted to an unsaturated bond, or the like,i.e., a ring represented by

each of Y′ and Y″ represents carbon, sulfur or oxygen (preferably,carbon) atom; and Y and n are as defined above.

More preferred examples include:

Further, in the above formula, the compound wherein at least one of Y′or Y″ represents nitrogen atom, for example,

wherein each symbol is as defined above, or a salt thereof can beproduced by the process as described hereinafter and has the activitiesas described hereinafter.

The Y-containing optionally substituted 5- to 8-membered ring whose ringconstituent atoms contain no nitrogen atom may further have 1 to 4substituents other than the substituent shown with respect to the Yportion, for example, the 1 to 4 same substituents as those defined withrespect to the substituent of the heterocyclic group of R¹ or R²;preferably, those selected from an aliphatic-chain hydrocarbon group[e.g., an alkyl group (preferably, a C₁₋₁₀ alkyl group), an alkenylgroup (preferably, a C₂₋₁₀ alkenyl group), an alkynyl group (preferably,a C₂₋₁₀ alkynyl group), an optionally substituted acyl group, a halogenatom, etc.; more preferably, a C₁₋₁₀ alkyl group (particularly, a C₁₋₆alkyl group) and a halogen atom (e.g., chlorine, bromine, iodine, orfluorine).

In the above-mentioned formula (I), ring A may have, at any possibleposition on its ring, 1 to 4, preferably one or two, more preferablyone, substituents that may be the same or different. As for saidsubstituent on ring A, there is employed, for example, a halogen atom,nitro group, an optionally substituted alkyl group, an optionallysubstituted hydroxyl group, an optionally substituted thiol group, anoptionally substituted amino group, an optionally substituted acylgroup, an optionally esterified carboxyl group, or an optionallysubstituted aromatic ring group.

Examples of the halogen atom as the substituent on ring A includefluorine, chlorine, bromine, and iodine.

Examples of the alkyl group of the optionally substituted alkyl group asthe substituent on ring A include any of a C₁₋₁₀ straight chain alkylgroup, a C₃₋₁₀ branched chain alkyl, and a C₃₋₁₀ cyclic alkyl, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orthe like.

Examples of the substituent in the optionally substituted alkyl group asthe substituent on ring A include the same substituent as that definedwith respect to the hydrocarbon group, acyl group, sulfonyl group, thesulfiniyl group or heterocyclic group represented by the above-mentionedR¹ or R².

Examples of the optionally substituted hydroxyl group as the substituenton ring A include an optionally substituted hydrocarbon group, anoptionally substituted acyl group, an optionally substituted carbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted heterocyclic groupor an optionally esterified carboxy group.

Examples of the substituents of the optionally substituted hydrocarbongroup, the optionally substituted acyl group, the optionally substitutedsulfonyl group, the optionally substituted sulfinyl group and theoptionally substituted heterocyclic group include the same substituentsas those of the optionally substituted hydrocarbon group, the optionallysubstituted acyl group, the optionally substituted sulfonyl group, theoptionally substituted sulfinyl group or the optionally substituted isheterocyclic group represented by the above-mentioned R¹ or R². Further,examples of the optionally substituted carbamoyl group and theoptionally esterified carboxy group include the same groups as thosedefined with respect to the substituents of the optionally substitutedhydrocarbon group, the optionally substituted acyl group, the optionallysubstituted sulfonyl group, the optionally substituted sulfinyl group orthe optionally substituted heterocyclic group represented by theabove-mentioned R¹ or R².

As the optionally substituted hydroxyl group as the substituent of ringA, preferably, there is a C₁₋₆ alkoxy group or hydroxyl group, morepreferably a C₁₋₆ alkoxy group, most preferably a C₁₋₃ alkoxy group, andparticularly, methoxy group.

Examples of the optionally substituted thiol group as the substituent ofring A include the same optionally substituted thiol group as thatdefined with respect to the substituent of the hydrocarbon group, theacyl group, the sulfonyl group, the sulfinyl group or the heterocyclicgroup represented by the above-mentioned R¹ or R².

Examples of the optionally substituted amino group as the substituent ofring A include the same optionally substituted amino group as thatdefined with respect to the substituent of the hydrocarbon group, theacyl group, the sulfonyl group, the sulfinyl group or the heterocyclicgroup represented by the above-mentioned R¹ or R².

Examples of the optionally substituted acyl group as the substituent ofring A include the same optionally substituted acyl group as thatrepresented by the above-mentioned R¹ or R².

Examples of the optionally esterified carboxyl group as the substituentof ring A include the same optionally esterified carboxyl group as thatdefined with respect to the substituent of the hydrocarbon group, theacyl group, the sulfonyl group, the sulfinyl group or the heterocyclicgroup represented by the above-mentioned R¹ or R².

Examples of the optionally substituted aromatic ring as the substituenton ring A include a C₆₋₄ aromatic hydrocarbon group such as phenyl,naphthyl, anthryl, or the like as well as a 5- to 7-memberedhetero-aromatic residue having heteroatoms(s) selected from nitrogen,sulfur, and oxygen, such as pyridyl, furyl, thienyl, imidazolyl,thiazolyl, or the like.

The substituent(s) on ring A are located preferably at the 3-positionand/or 4-position on ring A. In the case where these substituents onring A are adjacent each other, the adjacent substituents may becombined to form a ring represented by —(CH₂)_(m)— or —O—(CH₂)₁—O—[wherein, m represents an integer of 3 to 5 and 1 represents an integerof 1 to 3]. Such a ring includes a 5- to 7-membered ring that is formedwith the carbon atoms in the benzene ring.

It is preferred that ring A is substituted with at least one optionallysubstituted hydroxyl group, preferably a C₁₋₆ alkoxy group or hydroxylgroup, more preferably a C₁₋₆ alkoxy group, most preferably a C₁₋₃alkoxy group, in particular, methoxy group. More preferably, ring A issubstituted with one optionally substituted hydroxyl. Specifically, forexample, it is preferred that the 4-position in ring A is substitutedwith an optionally substituted hydroxyl group (particularly, methoxygroup).

Preferred examples of the compound represented by the above-mentionedformula (I) include a compound, wherein alk is methylene, G is a halogenatom such as chlorine atom, etc., X is —(CH₂)_(q)— (q represents aninteger of 0 to 5), R is an optionally substituted amino group; ring Bis an optionally substituted 5- to 8-membered ring containing Y, Y is anoptionally substituted sulfur atom or

and ring A is substituted with a C₁₋₆ alkoxy group or hydroxyl group, aprodrug thereof or a salt thereof; more preferably a compound, whereinalk is methylene, G is a halogen atom such as chlorine atom, etc., X is—(CH₂)_(q)— (q represents 0, i.e., a bond), R is

(wherein C is as defined above), ring B is a ring represented by

[wherein Y′ and Y″ represent carbon, sulfur, oxygen atom (preferablycarbon), respectively and Y and n are as defined above (preferably anoptionally oxidized sulfur atom or

n is as defined above (preferably 1)] which may be substituted with 1 to4 substituents selected from a C₁₋₆ alkyl group and a halogen atom, andring A is substituted with a C₁₋₆ alkoxy group or hydroxyl group(preferably substituted with a C₁₋₆ alkoxy group at the 4-position inring A), a prodrug thereof or a salt thereof.

Preferably examples of such a compound include;

3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione,an optically active substance thereof or a salt thereof;

3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dione,an optically active substance thereof or a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,an optically active substance thereof or a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-(2,5-pyrrolidinedioneor a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dioneor a salt thereof;

1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

2-aminomethyl-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine, an optically active substance thereof ora salt thereof;

1-{[3-chloro-4-(4-hydroxyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof;

4-{3-chloro-2-(2,5-dioxo-1-pyrrolidinyl)methyl}-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyldiisobutyl phosphate or a salt thereof; or

butyl4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methul]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenylcarbonate or a salt thereof.

In addition, preferred examples of the compound represented by theabove-mentioned formula (I) include a compound, wherein G is chloridneatom, X is —(CH₂)_(q)— (q represents an integer of 0 to 5. ), R is anoptionally substituted amino group, ring B is a Y containing optionallysubstituted 5- to 8-membered ring, Y is

(wherein, Ra and Rb, which may be the same or different, respectively,represent hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfonyl group, an optionallysubstituted sulfinyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally esterified carboxylgroup, or an optionally substituted heterocyclic group, or Ra and Rb maybe combined each other to form a 5- to 7-membered ring), and ring A issubstituted with a C₁₋₆ alkoxy group. Example of such a compoundinclude:

3-chloro-2-[(2,5-dioxopyrrolidin-1-yl)methyl]-5,6,7,8-tetrahydro-7-oxo-4-(4-methoxyphenyl)[1]-benzothieno[2,3-b]pyridineethylene ketal or a salt thereof, or the like.

As for a salt of the compound represented by the formula (I) in thepresent invention [hereinafter referred to as compound (I)] and a saltof the starting compound for the production of compound (I), apharmaceutically acceptable salt is preferred. Examples thereof includea salt with an inorganic base, a salt with an organic base, a salt withan inorganic acid, a salt with an organic acid, a salt with a basic oracidic amino acid, and the like. Preferred examples of the salt with aninorganic base include alkali metal salts such as the sodium salt, thepotassium salt, and the like; alkaline earth metal salts such as thecalcium salt, the magnesium salt, and the like; as well as an aluminumsalt, an ammonium salt, and the like. Preferred examples of the saltwith an organic base include salts with trimethylamine, triethylamine,pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N′-dibenzylethylenediamine, and the like. Preferredexamples of the salt with an inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, and the like. Preferable examples of the salt with anorganic acid include salts with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferableexamples of the salt with a basic amino acid include salts witharginine, lysine, ornithine and the like. Preferable examples of thesalt with an acidic amino acid include salts with aspartic acid,glutamic acid, and the like.

Compound (I) or its salt may be in the form of a prodrug thereof. Theprodrug of compound (I) or its salt refers to a compound that isconverted into compound (I) or its salt by a reaction with an enzyme,gastric acid, or the like under a physiological condition in the livingbody, namely, [1] a compound that is converted into compound (I) or itssalt by an enzymatic oxidation, reduction, hydrolysis, or the like and[2] a compound that is converted into compound (I) or its salt byhydrolysis with gastric acid or the like. Examples of the prodrug ofcompound (I) or its salt include a compound or its salt, wherein thehydroxyl group in compound (I) or its salt is acylated, alkylated,phosphorylated, or converted into the borate (e.g., a compound or itssalt, wherein the hydroxyl group in compound (I) or its salt isconverted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy,succinyloxy, fumaryloxy, alanyloxy, or dimethylaminomethylcarbonyloxy,etc.), a compound or its salt, wherein the carboxyl group in compound(I) or its salt is esterified or amidated (e.g., a compound or its saltor the like, wherein the carboxyl group in compound (I) or its salt issubjected to ethyl esterification, phenyl esterification,carboxyoxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methylesterification, cyclohexyloxycarbonyl esterification, or conversion intothe methyl amide), and the like. These prodrugs can be producedaccording to a per se known method or its modified method.

Moreover, the prodrug of compound (I) or its salt may be a compound thatis converted into compound (I) or its salt under a physiologicalcondition as described in “Iyakuhin no Kaihatu (Development of Drugs)”,Vol. 7, Bunishi Sekkei (Molecular Design), Hirokawa Shoten, 1990, pages163-198.

Compound (I) or its salt may be labeled with an isotope (e.g., ³H, ¹⁴C,³⁵S, ¹²⁵I, etc.) or the like.

When compound (I) of the present invention is a racemate, it can beseparated into the corresponding (S)-form and (R)-form according to aconventional optical resolution method. The present invention includeseach optically active substance (compound) and a racemate.

The above-mentioned compound (I) can be produced in the followingmanner. That is,

Process A

wherein alk represents an optionally substituted lower alkylene group; Qrepresents a leaving group; X¹ represents oxygen atom or an optionallyoxidized sulfur atom; and the other symbols are as defined above.

In the general formula (II-1), examples of the leaving group representedby Q include halogen, preferably chlorine, bromine, or iodine, and ahydroxyl group activated by esterification such as a residue of organicsulfonic acid (e.g., p-toluenesulfonyloxy group, methansulfonyloxygroup, etc.), a residue of organic phosphoric acid such asdiphenylphosphoryloxy group, dibenzylphosphoryloxy group,dimethylphosphoryloxy group, and the like.

In this process, (II-1) is reacted with (III) in the presence of a baseto produce (I-1). The reaction of (II-1) with (III) is carried out in anappropriate solvent. Examples of said solvent include aromatichydrocarbon such as benzene, toluene, xylene, etc.; ether such asdioxane, tetrahydrofuran (THF), dimethoxyethane, or the like; alcoholsuch as methanol, ethanol, propanol, etc.; ethyl acetate; acetonitrile;pyridine; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO);chloroform; dichloromethane; 1,2-dichloroethane;1,1,2,2,-tetrachloroethane; acetone; 2-butanone; and a mixture thereof.The reaction of (II-1) with (III) is carried out in the presence of anappropriate base such as an alkali metal salt, for example, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,sodium hydrogen carbonate, etc.; silver carbonate (Ag₂CO₃); sodiumhydride; potassium hydride; an amine, for example, pyridine,triethylamine, N,N-dimethylaniline, 1,5-diazabicyclo[4.3.0]non-5ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),etc.; or the like. The amount of the base to be used is preferably about1-5 molar equivalents for compound (II-1). This reaction is carried outusually at −20° C. to 150° C., preferably −10° C. to 100° C.

The thus-obtained thienopyridine derivative (I-1) can be isolated andpurified by a known separation and purification means, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Process B

wherein each symbol is as defined above.

In this process, (II-2) is reacted with (IV) in the presence of a baseto produce (I-2). The reaction of (II-2) with (IV) is carried out in anappropriate solvent. Examples of said solvent include aromatichydrocarbon such as benzene, toluene, xylene, etc.; ether such asdioxane, tetrahydrofuran, dimethoxyethane, etc.; alcohol such asmethanol, ethanol, propanol, etc.; ethyl acetate; acetonitrile;pyridine; N,N-dimethylformamide (DMF); dimethylacetamide (DMA); dimethylsulfoxide (DMSO); 1-methyl-2-pyrrolidone;1,3-dimethyl-2-imidazolidinone; chloroform; dichloromethane;1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; acetone; 2-butanone; anda mixture thereof. The reaction of (II-2) with (IV) is carried out inthe presence of an appropriate base such as an alkali metal salt, forexample, sodium hydroxide, potassium hydroxide, potassium carbonate,sodium carbonate, sodium hydrogen carbonate, etc.; a metal alkoxide suchas sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassiumtert-butoxide, etc.; an amine for example, pyridine, triethylamine,N,N-dimethylaniline, etc., sodium hydride; potassium hydride; or thelike. The amount of the base to be used is preferably about 1-5 molarequivalents for compound (II-2). This reaction is carried out usually at−20° C. to 150° C., preferably −10° C. to 100° C. The present reaction,also, is carried out by using an excess amount of (IV) as the base.

The thus-obtained thienopyridine derivative (I-2) can be isolated andpurified by a known separation and purification means such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Process C

[wherein ring B¹ represents the formation of a Y¹-containing optionallysubstituted 5- to 8-membered ring whose ring constituent atoms containno nitrogen atom; Y¹ represents sulfur atom or

and the other symbols are as defined above.

In this process, (I-3) is subjected to oxidation to produce (I-4). Thisreaction is carried out in an appropriate solvent in the presence of anoxidizing agent or, if necessary, a catalyst. Examples of said solventinclude a high polar aprotic solvent such as 1-methyl-2-pyrrolidone,1,3-dimethyl-2-imidazolidinone, dimethylformamide, dimethylacetamide,dimethyl sulfoxide, etc.; aromatic hydrocarbon such as benzene, toluene,xylene, etc.; ether such as dioxane, tetrahydrofuran, dimethoxyethane,etc.; ethyl acetate; chloroform; dichloromethane; 1,2-dichloroethane;1,1,2,2,-tetrachloroethane; and a mixture thereof. As the oxidizingagent, for example, there is hydrogen peroxide solution, peracetic acid,metachloroperbenzoic acid, cumene hydroperoxide, tert-butylhydroperoxide, activated DMSO, manganese dioxide, nitric acid, or thelike. As the catalyst, preferably, a complex containing a metal is used.Examples of the metal include vanadium, titanium, ruthenium, rhenium,tungsten, manganese, cobalt, etc. Among them, vanadium is preferred.Examples of the vanadium complex include vanadium oxides such asvanadium oxide acetylacetonate, vanadium oxide benzoylacetonate,vanadium oxide picolinate, vandium (V) oxide, vanadium (IV) oxideacetate, vanadium (IV) oxide sulfate hydrate, etc.; vanadium nitridessuch as vanadium nitride; vanadium chlorides such as vanadiumoxytrichloride, vanadium dichloride, vanadium tetrachloride, etc.;vanadium oxide trimethoxide; vanadium oxide triethoxide; vanadium oxidetri-n-propoxide; vanadium oxide triisopropoxide, vanadiumtri-n-butoxide; vanadium oxide tri-sec-butoxide; vanadiumoxide-t-butoxide; vanadium oxide β-hydroxyquinolyl; vanadium oxideβ-hydroxypyridyl; and the like. The amount of the oxidizing agent ispreferably an equivalent or an excess amount (for example, about 1-50molar equivalents) for compound (I-3). Further, the amount of thecatalyst to be used is 0.0000001 to 10 equivalents, preferably 0.0000005to 1 equivalent for compound (I-3). This reaction is carried out usuallyat −70° C. to 150° C., preferably -60° C. to 120° C. and the reactiontime is usually 1-100 hours.

The thus-obtained thienopyridine derivative (I-4) can be isolated andpurified by a known separation and purification means such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Process D

wherein Z¹ represents an optionally substituted heterocyclic group; q′represents an integer of 0 to 4; G′ represents a halogen atom; and theother symbols are as defined above.

In this process, the compound represented by the general formula (II-3)is first reacted with a corresponding amount of triphenylphosphine toproduce a phosphonium salt derivative represented by the general formula(VI). This reaction is carried out in a solvent and examples of saidsolvent include aromatic hydrocarbon such as benzene, toluene, xylene,etc.; ether such as tetrahydrofuran, dioxane, dimethoxyethane, etc.;acetonitrile; and a mixture thereof. This reaction is carried out at 10°C. to 200° C., preferably 30° C. to 150° C. for 0.5-50 hours.

Then, the phosphonium salt derivative (VI) and an aldehyde derivative(VII) are subjected to condensation reaction to produce (VIII). Thecondensation reaction of (VI) and (VII) is carried out in an appropriatesolvent in the presence of a base. Examples of said solvent includealcohol such as methanol, ethanol, propanol, etc.; ether such as ethylether, dioxane, tetrahydrofuran, dimethoxyethane, etc.; aromatichydrocarbon such as benzene, toluene, xylene, etc.; dichloromethane;1,2-dichloroethane; N,N-dimethylformamide; dimethyl sulfoxide; and amixture thereof. Examples of the base include an alkali metal hydridesuch as sodium hydride, potassium hydride, etc.; an alkoxide such assodium ethoxide, sodium methoxide, potassium ethoxide, potassiumtert.-butoxide, etc.; an organic lithium compound such as methyllithium,butyllithium, phenyllithium, etc.; sodium amide; and the like. Theamount of the base to be used is preferably about 1-1.5 molarequivalents for compound (VI). This reaction is carried out usually at−50° C. to 100° C., preferably −20° C. to 50° C. The reaction time is0.5-20 hours.

Although (VIII) is obtained as an isomeric mixture of the (E) form andthe (Z) form with respect to the newly formed double bond, these (E) and(Z) forms, after separation into each isomer or as a mixture thereofwithout separation, are subjected to reduction to produce (I-5). Thisreduction is carried out by a conventional method in a solvent under anatmosphere of hydrogen in the presence of a catalyst such as a palladiumcatalyst (palladium-carbon, palladium black, etc.), a platinum catalyst(platinum dioxide, etc.), Raney nickel, or the like. Examples of saidsolvent include alcohol such as methanol, ethanol, propanol, etc.; ethersuch as ethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, etc.;aromatic hydrocarbon such as benzene, toluene, xylene, etc.;dichloromethane; 1,2-dichloroethane; ethyl acetate; acetonitrile;acetone; 2-butanone; N,N-dimethylformamide; dimethyl sulfoxide; and amixture thereof. The pressure of hydrogen atmosphere is 1-150atmospheric pressure, preferably 1-20 atmospheric pressure. Thethus-obtained thienopyridine derivative (I-5) can be isolated andpurified according to a known separation and purification means such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Process E

wherein each symbol is as defined above.

In this process, (II-1) is reacted with an alkali metal salt ofdiformylimide such as the sodium salt of diformylimide to be convertedinto a formylamino compound (I-6), which is then reacted with an acid toproduce (I-7).

The reaction of compound (II-1) with an alkali metal salt ofdiformylimide such as the sodium salt of diformylimide is carried out inthe same manner as that in Process A.

Compound (I-7) is produced by subjecting the formylamino compound (I-6)to hydrolysis in the presence of an acid. The hydrolysis of compound(I-6) is carried out in a water-containing solvent. Examples of saidsolvent include ether such as dioxane, tetrahydrofuran, dimethoxyethane,etc.; alcohol such as methanol, ethanol, propanol, butanol,2-methoxyethanol, etc.; acetonitrile; N,N-dimethylformamide; dimethylsulfoxide; acetone; 2-butanone; acetic acid; and a mixture thereof. Theacid is, for example, hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, or the like. The amount of the acid to be used ispreferably a large excess amount, e.g., about 5-50 molar equivalents forcompound (I-6). This reaction is carried out usually at 30° C. to 150°C., preferably about 50° C. to 120° C. and the reaction time is usually1-100 hours. Furthermore, the sulfonylamino derivative of compound (I-7)is produced according to Process F described in JP 10-36374 A, and theacylamino derivative thereof is produced according to its Process I.

The thus-obtained thienopyridine derivative can be isolated and purifiedby a known separation and purification means such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Compound (I-7) obtained by Process E is also produced by the Gabrielmethod, wherein compound A, obtained by the reaction of compound (II-1)with an alkali metal salt of phthalimide such as the potassium salt ofphthalimide, is decomposed by the reaction thereof with an acid orhydrazine (Process F).

Process F

wherein each symbol is as defined above.

The reaction of compound (II-1) with an alkali metal salt of phthalimidesuch as the potassium salt of phthalimide is carried out in the samemanner as that of Process A. Compound (I-7) is produced by subjecting todecomposition reaction in the presence of an acid or hydrazine. Thedecomposition reaction of compound (I-8) is carried out in the presenceof water. As for said solvent, there can be used the same solvent asthat used in the hydrolysis of compound (I-6) in Process E. As for saidacid, there can be used hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, or the like.

The thus-obtained thienopyridine derivative (I-7) and (I-8) can beisolated and purified by a known separation and purification means suchas concentration, concentration under reduced pressure, solventextraction, crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Process G

wherein each symbol is as defined above.

In this method, (II-1) is reacted with (XII) in the presence of a baseto produce (I-9). The reaction of (II-1) with (XII) is carried out in anappropriate solvent. Examples of said solvent include aromatichydrocarbon such as benzene, toluene, xylene, and the like; ether suchas dioxane, tetrahydrofuran, dimethoxyethane, and the like; alcohol suchas methanol, ethanol, propanol, and the like; ethyl acetate;acetonitrile; pyridine; N,N-dimethylformamide (DMF); dimethyl sulfoxide(DMSO); chloroform; dichloromethane; 1,2-dichloroethane;1,1,2,2,-tetrachloroethane; acetone; 2-butanone; and a mixture thereof.The reaction of (II-1) with (XII) is carried out in the presence of anappropriate base such as an alkali metal salt, for example, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,sodium hydrogen carbonate, or the like; an amine such as pyridine,triethylamine, N,N-dimethylaniline, or the like; sodium hydride;potassium hydride; n-butyllithium; t-butyllithium; lithiumdiisopropylamide (LDA); or the like. The amount of the base to be usedis preferably about 1-5 molar equivalents for compound (II-1). Thisreaction is carried out usually at −70° C. to 150° C., preferably −70°C. to 100° C. This reaction is also carried out by the use of an excessamount of (XII) as the base.

The thus-obtained thienopyridine derivative (I-9) can be isolated andpurified by a known separation and purification means such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, trans-solubilization,chromatography, and the like.

Further, the compound represented by the general formula (II-1), whichis the starting material in the above-mentioned Process A, Process E,Process F, and Process G, can be produced, for example, in the followingmanner.

wherein each symbol is as defined above.

According to a process described in Journal of Medicinal Chemistry, 17,624 (1974), compound (XI) is produced by reaction of compound (IX),sulfur, and compound (X) in the presence of a base in a solvent.Examples of said solvent include aromatic hydrocarbon such as benzene,toluene, xylene, and the like; ether such as dioxane, tetrahydrofuran,dimethoxyethane, and the like; alcohol such as methanol, ethanol,propanol, and the like; chloroform; dichloromethane; 1,2-dichloroethane;1,1,2,2,-tetrachloroethane; N,N-dimethylformamide (DMF);dimethylacetamide (DMA); dimethyl sulfoxide (DMSO);1-methyl-2-pyrrolidone; 1,3-dimethyl-2-imidazolidinone; and a mixturethereof. The reaction is carried out in the presence of an appropriatebase such as an alkali metal salt such as sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate,etc.; a metal alkoxide such as sodium methoxide, sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide, etc.; an amine such astriethylamine, diethylamine, morpholino, piperidine,N,N-dimethylaniline, or the like. The amount of this base is preferablyabout 1-5 molar equivalents for compound (IX). This reaction is carriedout usually at −20° C. to 150° C., preferably −10° C. to 100° C. Then,compound (II-1) is produced by the reaction of compound (XI) andcompound (XII). The reaction of (XI) and (XII) is carried out in asolvent in the presence of an appropriate acid such as a Lewis acid, forexample, aluminum chloride, zinc chloride, or the like; hydrochloricacid; sulfuric acid; trifluoroacetic acid; p-toluenesulfonic acid; orthe like. Examples of said solvent include aromatic hydrocarbon such asbenzene, toluene, xylene, and the like; ether such as dioxane,tetrahydrofuran, dimethoxyethane, and the like; alcohol such asmethanol, ethanol, propanol, and the like; ethyl acetate;N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); chloroform;dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; and amixture thereof. The amount of compound (VIII) to be used is preferablyabout 1.0-2.0 molar equivalents for compound (VII). The amount of theacid is preferably about 0.05-2.0 molar equivalents for compound (VII).This reaction is carried out usually at 0° C. to 200° C., preferablyabout 20° C. to 120° C. The reaction time is 0.5-20 hours, preferably1-10 hours.

The thus-obtained compound represented by the general formula (II-1) canbe isolated and purified by a known separation and purification meanssuch as concentration, concentration under reduced pressure, solventextraction, crystallization, recrystallization, trans-solubilization,chromatography, and the like.

In the case where the thienopyridine derivatives produced by Process Ato Process G have isopropoxy group as a substituent on ring A, theisopropoxy group can be converted into hydroxyl group by treatment withtitanium tetrachloride. This reaction is carried out in a solvent suchas chloroform, dichloromethane, carbon tetrachloride, or the like at−50° C. to 30° C., preferably about −10° C. to 20° C.

Since compound (I) or a salt thereof of the present invention hasanti-inflammatory activity and further anti-arthritic activity, it canbe used in the prevention or treatment of all arthritic diseases withinflammatory conditions in joints. The arthritic diseases include, forexample, chronic rheumatoid arthritis and the like.

Also, compound (I) of the present invention or a salt thereof can beused in the prevention and treatment of rheumatism and the like.

Further, compound (I) of the present invention or a salt thereof hasexcellent suppressing effect on bone resorption and is useful in theprevention and treatment of bone destruction, osteoporosis, and thelike, which accompany arthritis. Furthermore, the compound of thepresent invention has suppressing effect on immune cytokine productionand is also useful in the prevention and treatment of diseasesassociated with immune reactions, and/or in the prevention and treatmentof rejection reaction after organ transplantation.

Furthermore, compound (I) of the present invention or a salt thereof hassuppressing effect on the production of immune cytokines [e.g.,interleukin-2 (IL-2), interferon-γ (IFN-γ), etc.] and is useful in theprevention and treatment of diseases associated with immune includingautoimmune diseases.

Examples of these diseases include systemic lupus erythematosus,inflammatory bowel disease (ulcerative colitis, Crohn's disease),multiple sclerosis, psoriasis, chronic hepatitis, urinary bladdercarcinoma, breast carcinoma, uterine cervix carcinoma, chroniclymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer,colon cancer, rectal cancer, infection with Helicobacter pylori,Hodgkin's disease, insulin-dependent diabetes mellitus, malignantmelanoma, multiple myeloma, non Hodgkin's lymphoma, non-small cell lungcarcinoma, ovarian cancer, peptic ulcer, prostatic carcinoma, septicshock, tuberculosis, sterility, arteriosclerosis, Behcet's disease,asthma, atopic dermatitis, nephritis, systemic mycosis, acute bacterialmeningitis, acute myocardial infarction, acute pancreatitis, acute viralencephalitis, adult respiratory distress syndrome, bacterial pneumonia,chronic pancreatitis, herpes simplex virus infection, varicella-zostervirus infection, AIDS, human papilloma virus infection, influenza,invasive staphylococcal infection, peripheral vascular diseases, sepsis,interstitial hepatic diseases, regional ileitis, and the like. Compound(I) of the present invention or a salt thereof is used, among others, inprevention or treatment of lupus erythematosus, chronic hepatitis,interstitial hepatic diseases, asthma, psoriasis, ulcerative colitis,Crohn's disease, regional ileitis, multiple sclerosis, or the like.

Also, compound (I) of the present invention or a salt thereof is usefulin the prevention and treatment of rejection reaction after organtransplantation.

Moreover, compound (1) of the present invention or a salt thereof isuseful as a T-cell differentiation modifying drug. A T-celldifferentiation modifying drug is a generic name of a compound whichmodifies differentiation of T lymphocyte into Type-1 T lymphocyte (T1cell) or Type-II T lymphocyte (T2 cell). T1 cells are T lymphocytesmainly producing IFN-γ, IL-2 and TNFβ as cytokines, and include CD4⁺ Tlymphocytes and CD8⁺ T lymphocytes. T2 cells are T lymphocytes mainlyproducing IL-4, IL-5 and IL-10 as cytokines and include CD4⁺ Tlymphocytes and CD8⁺ T lymphocytes. Therefore, a T-cell differentiationmodifying drug can be used for preventing or treating arthritis and theabove-mentioned other diseases.

The toxicity of the compound of the present invention is low.

Therefore, compound (I) of the present invention or a salt thereof maybe used as prophylactic and therapeutic drugs of inflammatory diseases,arthritis, rheumatism, rheumatoid arthritis, or autoimmune diseases; asprophylactic and therapeutic drugs of rejection reaction after organtransplantation; and as prophylactic and therapeutic drugs of bonedestruction, osteoporosis, and the like, which accompany arthritis, inmammalian animals including human being (e.g., human being, horse, cow,pig, dog, cat, rat, mouse, etc.).

The dosage of compound (I) and a salt thereof can be selected in variousways depending on the administration route and the symptom of thepatient to be treated. Usually, as compound (I) per an adult, the dailydosage can be selected from a range of about 1 mg to about 500 mg,preferably about 5 mg to about 100 mg in the case of oraladministration, and from a range of about 0.1 mg to about 100 mg,further preferably about 0.3 mg to about 10 mg in the case of parenteraladministration. The dosage can be administered by dividing 1-3 times perday.

The compound (I) or a salt thereof of the present invention can becompounded with a pharmaceutically permissible carrier and can be orallyor parenterally administered as solid formulations such as tablets,capsules, granules, powders, or the like; or liquid formulations such assyrups, injections, or the like. Also, there can be preparedformulations for transdermal administration such as patchings,cataplasms, ointments (including creams), plasters, tapes, lotions,solutions, suspensions, emulsions, sprays, and the like.

As for the pharmaceutically acceptable carrier, a variety of organic orinorganic carrier substances, which have been conventionally employed asformulation materials, are used, and are compounded as an excipient, alubricant, a binding agent, and a disintegrator in solid formulations; asolvent, a solubilizing agent, a suspending agent, an isotonic agent, abuffering agent, and an analgesic in liquid formulations. Also, asneeded, formulation additives such as a preservative, an antioxidant, astabilizer, a coloring agent, a sweetening agent, and the like can beused.

Preferred examples of the excipient include lactose, sucrose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid,and the like. Preferred examples of the lubricant include magnesiumstearate, potassium stearate, talc, colloidal silica, and the like.Preferable examples of the binding agent include crystalline cellulose,α-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like.Preferable examples of the disintegrator include starch, carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose,and the like. Preferable examples of the solvent include water forinjection, alcohol, propylene glycol, macrogol, sesame oil, corn oil,and the like.

As needed, for the purpose of taste masking, enteric coating, orprolonged action, oral formulations can be coated by a per se knownmethod. Examples of this coating agent include hydroxypropylmethylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68[polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate phthalate, Eudragit (manufactured by Rohm Company,methacrylic acid-acrylic acid copolymer), and the like.

Preferred examples of the solubilizing agent include polyethyleneglycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, and thelike. Preferred examples of the suspending agent include surfactantssuch as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate, etc.; hydrophilic high molecular weightsubstances such as polyvinyl alcohol, polyvinyl pyrrolidone, sodiumcarboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose,hydroxyethyl cellulose hydroxypropyl cellulose, etc.; and the like.Preferred examples of the isotonic agent include sodium chloride,glycerin, D-mannitol, and the like. Preferred examples of the bufferingagent include buffer solutions of a phosphate, an acetate, a carbonate,a citrate, or the like. Preferred examples of the analgesic includebenzyl alcohol and the like. Preferred examples of the preservativeinclude paraoxybenzoic acid ester, chlorobutanol, benzyl alcohol,phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.Preferred examples of the antioxidant include sulfite, ascorbic acid,and the like.

Moreover, compound (I) or a salt thereof can be administered as a singleformulation, or simultaneously or at temporal intervals together with[1] a cyclooxygenase inhibitor (a Cox-I, Cox-II inhibitor), [2] adisease-modifying anti-rheumatic drug and an immunodepressant, [3] abiological preparation, [4] an analgesic and an anti-inflammatory agent,[5] a therapeutic drug for bone disease, [6] p38MAP kinase inhibitorand/or TNF-α production inhibitor, [7] c-JUN N-terminal kinase (JNK)inhibitor, or the like.

[1] Examples of cyclooxygenase inhibitors (Cox-I, Cox-II inhibitors)include celecoxib, rofecoxib, salicylic acid derivatives such asaspirin, diclofenac, indomethacin, loxoprofen, and the like. The oraldoses of these drugs are, for example, about 100-200 mg/day forcelecoxib, about 10-30 mg/day for rofecoxib, 1000-4500 mg/day forsalicylic acid derivatives such as aspirin, about 25-75 mg/day fordiclofenac, about 50-150 mg/day for indomethacin, and about 60-180mg/day for loxoprofen.

[2] Examples of disease-modifying anti-rheumatic drugs andimmunodepressants include methotrexate, leflunomide, prograf,sulfasalazine, D-penicillamine, oral gold compounds, and the like. Theoral doses of these drugs are, for example, about 2.5-7.5 mg/week formethotrexate, about 20-100 mg/day for leflunomide, about 1-5 mg/day forPrograf, about 500-2000 mg/day for sulfasalazine, about 100-600 mg/dayfor D-penicillamine, and about 3-6 mg/day for oral gold compounds.

[3] Examples of biological preparations include monoclonal antibodies(e.g., anti-TNF-α antibody, anti-IL-12 antibody, anti-IL-6 antibody,anti-ICAM-I antibody, anti-CD4 antibody, etc.), soluble receptors (e.g.,soluble TNF-α receptor, etc.), and protein ligands (IL-1 receptorantagonist, etc.). The oral doses of these drugs are, for example, about0.1-50 mg/kg/day, preferably 0.5-20 mg/kg/day.

[4] Examples of analgesics and anti-inflammatory agents includecentrally acting analgesics (e.g., morphine, codeine, pentazocine,etc.), steroids (e.g., prednisolone, dexamethasone, betamethazone,etc.), and anti-inflammatory enzyme agents (e.g., bromelain, lysozyme,proctase, etc.). The oral doses of these drugs are, for example, about1-1000 mg/day, preferably about 5-300 mg/day, for centrally actinganalgesics, about 0.1-400 mg/day, preferably about 5-100 mg/day, forsteroids, and about 1-100 mg/day, preferably about 5-40 mg/day, foranti-inflammatory enzyme agents.

[5] Examples of therapeutic drugs for bone diseases (e.g., bonefracture, refracture, osteoporosis, osteomalacia, Paget's disease ofbone, ankylosing spondylitis, chronic rheumatoid arthritis, denerativegonarthritis, destruction of joint tissues in related diseases, etc.)include calcium preparations (e.g., calcium carbonate, etc.), calcitoninpreparations, vitamin D preparations (e.g., α-calcidol, etc.), sexhormones (e.g., estrogen, estradiol, etc.), prostaglandin A₁,bisphosphonates, ipriflavons, fluorine compounds (e.g., sodium fluoride,etc.), vitamin K₂, bone morphogenic protein (BMP), fibroblast growthfactor (FGF), platelet-derived growth factor (PDGF), transforming growthfactor (TGF)-β, insulin-like growth factor-1 and -2 (IGF-1, -2),parathyroid hormone (PTH), and compounds described in European PatentPublications No. EP 376197 A1, EP 460488 A1, and EP 719782 A1(e.g.,(2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide,etc.).

[6] Examples of p38MAP kinase inhibitor and/or TNF-α inhibitor include:

i) a compound represented by the formula:

wherein R¹ is hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, or an optionallysubstituted amino group or an acyl group; R^(2′) is an optionallysubstituted pyridyl group; and R^(3′) is an optionally substitutedaromatic group, a salt thereof or a prodrug thereof;

ii) a compound represented by the formula:

wherein R^(1a) is hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an optionallysubstituted amino group or an acyl group; R^(2a) is an optionallysubstituted aromatic group; R^(3a) is hydrogen atom, an optionallysubstituted pyridyl group or an optionally substituted aromatichydrocarbon group; X^(a) is oxygen atom or an optionally oxidized sulfuratom; Y^(a) is a bond, oxygen atom, an optionally oxidized sulfur orNR^(4a) (wherein R^(4a) is hydrogen atom, an optionally substitutedhydrocarbon group or an acyl); and Z^(a) is a bond or an optionallysubstituted divalent straight chain hydrocarbon group, a salt thereof ora prodrug thereof; for example,

N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide;

N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide;

N-[4-[4-(4-methoxypheny)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide;

N-[4-[2-(4-fluoropheny)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;

N-[4-[2-ethyl-4-(3-methylpheny)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;

N-[4-[4-(3-methylpheny)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;

N-[4-[2-butyl-4-(3-methylpheny)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;

N-[4-[4-(3-methylpheny)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide;

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylbutylamide;

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;

N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;

N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;

N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;

N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;

N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;

N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine;

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;

N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;

N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;

N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;

N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;

N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;

N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;

N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)-amine;

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)-amine;

N-[4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;

(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide;

(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide;

(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;

(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;

(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;

(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;

(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;

(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;

N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]nicotinamide;

N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;

N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;

N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;

N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]nicotinamide;

N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;

N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;

N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;

(S)-N-(l-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(R)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine;

(R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine;

(S)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(R)-N-(l-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(S)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

(R)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;

or a salt thereof;

iii) a compound represented by the formula:

wherein a is N or C; b is CH when a is N, or O when a is C; ═ is a bondor a double bond depending upon whether the azole ring being imidazolering or oxazole ring; Z_(b) is N or CH; W_(b) is —NR_(6b)—Y_(b)— (R_(6b)is H, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₃ alkyl, C₆₋₁₈aryl, C₃₋₁₈ heteroalkyl, C₇₋₁₉ aralkyl or C₄₋₁₉ heteroaralkyl; —Y_(b)—is C₁₋₄ alkylene or a bond), —O— or —S—; R_(2b) is phenyl (optionallysubstituted with 1 or more substitutes selected from the groupconsisting of a halogen atom, trifluoromethyl, cyano, amide, thioamide,carboxylate, thiocarboxylate, C₁₋₄ alkoxy, amino, and mono- or di- C₁₋₄alkylamino); R₃b is H, a halogen atom, C₁₋₁₀ alkyl, C₁₋₄ alkenyl, C₃₋₁₀cycloalkyl, C₃₋₁₈ heterocycloalkly, C₆₋₁₈ aryl, C₃₋₁₈ heteroaryl, or—CH═N—NH—C(NH)NH₂ (each of which may be substituted with 1 to 4substituents selected from the group consisting of C₁₋₄ alkyl optionallysubstituted with hydroxyl, a halogen atom, C₁₋₄ alkyl substituted withhalogen, hydroxyl, C₁₋₄ alkoxy, C₁₋₄ alklthio, carboxy, carbonyloptionally substituted with C₁₋₆ alkyl or C₁₋₆ alkoxy, amino, mono- ordi- C₁₋₄ alkylamino, and 5- to 7-membered N-containing heterocyclicgroup (which may contain additional one or more hetero atoms)); andR_(5b) is C₆₋₁₈ aryl, C₃₋₁₈ heteroaryl or C₃₋₁₂ cycloalkyl (each ofwhich may be substituted 1 to 4 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkyl substituted with halogen, hydroxyl,C₁₋₄ alkyl, C₁₋₄ alkylthio, amino, mono- or di- C₁₋₄ alkylamino and a 5-to 7-membered N-containing heterocyclic group (which may containadditional one or more hetero atoms)), a salt thereof or a prodrugthereof; and the like.

[7] As the JNK inhibitor, there are, for example, the compoundsdescribed in WO 00/35906, WO 00/35909, WO 00/35921, WO 00/64872 and WO00/75118, and the like.

The present invention is further illustrated in more detail by thefollowing Reference Examples, Examples, and Test Example, but they arenot to be construed to restrict the present invention.

In the following description, Me represents methyl, Et represents ethyl,Ph represents phenyl, and Cbz represents benzyloxycarbonyl,respectively.

TEST EXAMPLE 1 Effect on Adjuvant Arthritis in Rats

The test compound was suspended in 0.5% methyl cellulose andadministered orally once daily for 14 days to male Lewis rats (7-weekold, Japan Clea), which had been sensitized by the intradermal injectionof 0.05 ml Freund's complete adjuvant (0.5% suspension of killedMycobacterium tuberculosis in liquid paraffin) into the right hindfootpad. Immediately before the sensitization (Day 0) and on 14 daysafter the administration (Day 14), the volume of the edema on the leftfootpad was measured by using a plethysmometer (manufactured by UgoBasile Company, Italy) and the suppression rate (%) of footpad swellingrelative to the unsensitized rats was calculated according to thefollowing equation.

Suppression rate of footpad swelling (%)={1-[(volume of footpad edema inthe treatment group)−(volume of footpad edema in the unsensitizedgroup)]/[(volume of footpad edema in the non-treatment group)−(volume offootpad edema in the unsensitized group)]}×100

The results were expressed by the mean±S.E. in each group (n=6) andtested by Dunnet's comparison with a significance level of 5%. As shownin Table 1, the compounds of the present invention exhibited efficacy insuppressing the footpad swelling.

TABLE 1 Suppression rate of Compound Dose footpad swelling (Example No.)(mg/kg/day) (%) 13 3.13 77** 22 3.13 88** **p < 0.01 vs. control

REFERENCE EXAMPLE 1

A mixture of 4-oxothiane (2.0 g), 4-methoxybenzoylactonitrile (describedin PCT International Application Publication No. WO99/65916) (3.0 g),sulfur (577 mg), morpholine (1.6 g) and ethanol (120 ml) was heatedunder reflux with stirring for 3 hours and then the solvent wasevaporated under reduced pressure. To the residue was added ethylacetate and the resulting solution was washed with 1 N hydrochloric acidand water, dried (MgSO₄), and then evaporated under reduced pressure toremove the solvent. The residue was subjected to column chromatographyon silica gel, and2-amino-4,5-dihydro-3-(4-methoxybenzoyl)-7H-thieno[2,3-c]thiopyran (3.6g, 69%) was obtained from the eluates with ethyl acetate-hexane (3:1) Itwas recrystallized from THF-hexane. Colorless prisms. Melting point of178-179° C.

According to the same manner, compounds in Reference Examples 2 to 9described in Table 2 were synthesized.

TABLE 2

Reference Melting Example point Recrystallization No. Y R (° C.) solvent1 S 4-MeO 178-179 THF-hexane 2 O 4-PhCH₂O 133-134 THF-hexane 3 H₂C═C4-MeO 153-154 Ethyl acetate- hexane   4^(a)) Me₂C═C 4-MeO Oil 5

4-MeO 161-162 THF-hexane 6 Me₂C 4-MeO 154-155 THF-hexane   7^(b))PhCH₂O—CH 4-MeO Oil 8 EtO₂C—CH 4-MeO 102-103 Ethyl acetate- hexane  9^(c)) PhCH₂O₂C—CH 4-MeO Oil ^(a)) ¹H NMR(CDCl₃) δ: 1.68(3H, s),1.69(3H, s), 1.97(2H, t, J=6.0Hz), 3.20(2H, t, J=6.0Hz), 3.30(2H, s),3.86(3H, s), 6.40(2H, br s), 6.90(2H, d, J=8.8Hz), 7.51(2H, d, J=8.8Hz);^(b)) ¹H NMR(CDCl₃) δ: 1.60-2.30(4H, m), 2.56-2.70(1H, m), 2.82-3.00(1H,m), 3.80-3.90(4H, m), 4.58(2H, s), 6.29(2H, s), 6.78-6.92(2H, m),7.30-7.36(5H, m), 7.48-7.53(2H, m); ^(c)) ¹H NMR(CDCl₃) δ: 1.55-1.74(1H,m), 1.88-2.12(3H, m), 2.70-2.89(3H, m), 3.85(3H, s), 5.14(2H, s),6.30(2H, br s), 6.89(2H, d, J=8.8Hz), 7.34(5H, s), 7.48(2H, d, J=8.8Hz).

REFERENCE EXAMPLE 10

According to the process described in Tetrahedron, 47, 1991, 3259, asolution of sodium amide (18.5 g) in THF (100 ml) was added to asolution of 1,4-cyclohexanedione monoethylene ketal (18.5 g) in THF (100ml) under a nitrogen atmosphere while keeping the temperature of thesolution at 10-20° C. After stirring at 20° C. for 30 minutes, methyliodide (41.3 g) was added and the stirring was continued at roomtemperature for 1 hour. The reaction solution was mixed with a saturatedaqueous solution of ammonium chloride (100 ml) and extracted withdiethyl ether. The diethyl ether layer was washed with water, dried(MgSO₄), and then evaporated under reduced pressure to remove thesolvent. The residue was subjected to column chromatography on silicagel and an oily mixture (mixture ratio of 1:1, 15.1 g) of4,4-ethylenedioxy-2-methyl-1-cyclohexanone and4,4-ethylenedioxy-2,2-dimethyl-1-cyclohexanone was obtained from theeluates with ethyl acetate-hexane (4:1). To a solution of this mixture(2.0 g) in ethanol (20 ml) was added sodium borohydride (440 mg) underice cooling. After stirring at room temperature for 2 hours, acetic acid(0.2 ml) was added, and the mixture was evaporated under reducedpressure to remove the solvent. To the residue was added ethyl acetateand the resulting solution was washed with water, dried (MgSO₄), andthen evaporated under reduced pressure to remove the solvent. Theresidue was subjected to column chromatography on silica gel to obtain4-hydoxy-3-methyl-1-cyclohexanone ethylene ketal (140 mg, ¹H NMR (CDCl₃)δ: 1.02 (3H, d, J=6.6 Hz), 1.20-2.00 (8H, m), 3.15-3.30 (1H, m), 3.94(4H, br s)) and 4-hydoxy-3,3-dimethyl-1-cyclohexanone ethylene ketal(470 mg, ¹H NMR (CDCl₃) δ: 1.00 (3H, s), 1.01 (3H,s), 1.35-1.90 (7H, m),3.38-3.46 (1H, m), 3.90-4.00 (4H, m)) from the eluates with ethylacetate-hexane (6:1) as oily substances, respectively.

REFERENCE EXAMPLE 11

To a solution of the compound obtained in Reference Example 10,4-hydoxy-3,3-dimethyl-1-cyclohexanone ethylene ketal, (372 mg) inTHF-DMF (5:1; 8 ml) was added sodium hydride (60% in oil, 160 mg) underice cooling. After stirring at the same temperature for 10 minutes,benzyl bromide (518 mg) and tetrabutylammonium iodide (369 mg) wereadded and the stirring was continued at room temperature for 11 hour.The reaction mixture was poured into water and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and then evaporated under reduced pressure to remove the solvent. Theresidue was subjected to column chromatography on silica gel to obtain4-benzyloxy-3,3-dimethyl-1-cyclohexanone ethylene ketal (360 mg, 65%) asan oily substance from the eluates with hexane-diethyl ether (4:1). ¹HNMR (CDCl₃) δ: 1.01 (3H, s), 1.03 (3H, s), 1.20-1.90 (6H, m), 3.07-3.12(1H, m), 3.90-3.93 (4H, m), 4.42 (1H, d, J=12.2 Hz), 4.64 (1H, d, J=12.2Hz), 7.25-7.40 (5H, m).

REFERENCE EXAMPLE 12

To a solution of the compound obtained in Reference Example 11 (360 mg)in THF (5 ml) was added 1 N aqueous hydrochloric acid (2.5 ml) at roomtemperature and the resulting solution was stirred at 50° C. for 2hours. The reaction mixture was poured into water and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then evaporated under reduced pressure to remove thesolvent. The residue was subjected to column chromatography on silicagel to obtain 4-benzyloxy-3,3-dimethyl-1-cyclohexanone (250 mg, 82%) asan oily substance from the eluates with hexane-diethyl ether (4:1). ¹HNMR (CDCl₃) δ: 0.95 (3H, s), 1.06 (3H, s), 2.00-2.30 (4H, m), 2.45-2.60(2H, m), 3.32-3.37 (1H, m), 4.52 (1H, d, J=11.6 Hz), 4.71 (1H, d, J=11.6Hz), 7.26-7.40 (5H, m).

REFERENCE EXAMPLE 13

A mixture of the compound obtained in Reference Example 12 (258 mg),4-methoxybenzoylacetonitrile (195 mg), sulfur (40 mg), morpholine (106mg), and ethanol (5 ml) was heated under reflux with stirring for 6hours, then poured into water, and extracted with ethyl acetate. Theethyl acetate layer was washed with a saturated aqueous solution ofammonium chloride and water, dried (MgSO₄), and then evaporated underreduced pressure to remove the solvent. The residue was subjected tocolumn chromatography on silica gel to obtain6-benzyloxy-2-amino-3-(4-methoxybenzoyl)-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[b]thiophene(170 mg, 36%) as an oily substance from the eluates with ethylacetate-hexane (4:1). ¹H NMR (CDCl₃) δ: 0.83-0.84 (6H, m), 1.74 (1H, d,J=16.4 Hz), 1.96 (1H, d, J=16.4 Hz), 2.58 (1H, dd, J=16.4, 6.6 Hz), 2.83(1H, dd, J=16.4, 5.2 Hz), 3.38 (1H, dd, J=6.6, 5.2 Hz), 3.87 (3H, s),4.49 (1H, d, J=12.0 Hz), 4.67 (1H, d, J=12.0 Hz), 6.16 (2H, br s),6.87-6.93 (2H, m), 7.25-7.40 (5H, m), 7.50-7.56 (2H, m).

REFERENCE EXAMPLE 14

Aluminum chloride (85 mg) was added to a mixture of the compoundobtained in Reference Example 13 (130 mg), 1,3-dichloroacetone (80 mg),and THF (10 ml) at room temperature and then the resulting mixture washeated under reflux with stirring for 15 minutes. The reaction mixturewas poured into water and extracted with ethyl acetate. The ethylacetate layer was washed with water, dried (MgSO₄), and then evaporatedunder reduced pressure to remove the solvent. The residue was subjectedto column chromatography on silica gel to obtain7-benzyloxy-3-chloro-2-chloromethyl-4,5,6,7-tetrahydro-6,6-dimethyl-(4-methoxyphenyl)[1]benzothieno[2,3-b]pyridine(25 mg, 16%) as an oily substance from the eluates with diethylether-hexane (1:8). ¹H NMR (CDC1₃) 67 : 0.78 (3H, s), 0.81 (3H, s), 1.59(1H, d, J=17.0 Hz), 1.83 (1H, d, J=17.0 Hz), 2.92 (1H, dd, J=17.6, 6.0Hz), 3.09 (1H, dd, J=17.6, 4.8 Hz), 3.37 (1H, dd, J=6.0, 4.8 Hz), 3.90(3H, s), 4.48 (1H, d, J=12.0 Hz), 4.66 (1H, d, J=12.0 Hz), 4.94 (2H, s),6.98-7.05 (2H, m), 7.10-7.22 (2H, m), 7.26-7.34 (5H, m).

REFERENCE EXAMPLE 15

Aluminum chloride (1.7 g) was added to a mixed solution of the compoundobtained in Reference Example 1 (2.0 g), 1,3-dichloroacetone (1.6 g),and THF (120 ml) at room temperature and then the resulting mixture washeated under reflux with stirring for 3 hours. The reaction mixture waspoured into a mixture of toluene (150 ml) and water (75 ml) withstirring and the stirring was continued for 2 hours. The organic layerwas separated, dried (MgSO₄), and then evaporated under reduced pressureto remove the solvent to obtain3-chloro-2-chloromethyl-(4-methoxyphenyl)-5,8-dihydro-8H-thiopyrano[4′,3′:4,5]-thieno[2,3-b]pyridine(2.1 g, 81%). It was recrystallized from ethyl acetate-hexane. Colorlessprisms. Melting point of 153-154° C.

According to the same manner, compounds of Reference Examples 16 to 24described in Table 3 were synthesized.

TABLE 3

Reference Melting Example point Recrystallization No. Y R (° C.) solvent15 S 4-MeO 153-154 Ethyl acetate- hexane 16 S 4-PhCH₂O 136-137 Ethylacetate 17 O 4-MeO 186-187 Ethyl acetate- hexane 18 H₂C═C 4-MeO 148-149Isopropyl ether 19 Me₂C═C 4-MeO 187-188 THF-hexane 20

4-MeO 219-229 THF-hexane 21 Me₂C 4-MeO 212-213 Ethyl acetate- hexane 22PhCH₂O—CH 4-MeO 121-122 Ethyl acetate- hexane 23 EtO₂C—CH 4-MeO 113-114Ethyl acetate- hexane 24 PhCH₂O₂C—CH 4-MeO 108-109 Ethyl acetate- hexane

REFERENCE EXAMPLE 25 4-Methoxybenzoylacetonitrile

To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide(21.6 L) were added sodium methoide (3.046 kg) and acetonitrile (2.135kg) and the mixture was stirred at 110° C. for 2 hours. Then, water(10.83 L) was added dropwise thereto at 15° C. or lower and furtheracetonitrile (14.4L) was added to the mixture. Then, 6 N HCl was addedthereto to adjust to pH 7.9 and the mixture was extracted with ethylacetate (72L). The aqueous layer was further extracted with ethylacetate (36.32 L). The organic layers were combined and concentrateduntil the content became 17.39 kg. Methanol (17.84 L) was added theretoand water (17.84 L) was added dropwise. Then, the mixture was stirred at5° C. for 1 hours and crystals deposited were filtered off and washedwith methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7g). ¹H-NMR (CDCl₃) δ:3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25Hz), 7.50 (2H, d, J=11.25 Hz).

REFERENCE EXAMPLE 262-Amino-4,5-dihydro-3-(4-metholybenzoyl)-7H-thieno[2,3-c]thiopyrane

To a mixture of 4-methoxybenzoylacetonitrile (6.283 kg), 4-oxothiane(5.00 kg), sulfur (1.157 kg) and ethanol (62.83 L) was added dropwisemorpholine 3.433 kg) with stirring. After stirring at 60° C. for 5.5hours, the mixture was cooled to 5° C. and stirred for one hour,Crystals deposited were filtered off, washed with cold ethanol (19.18 L)to obtain the titled compound as yellow crystals (9.557 kg, 88.9%).¹H-NMR (CDCl₃) δ: 2.31 (2H, t, J=5.4 Hz), 2.61 (2H, t, J=5.4 Hz), 3.65(2H, s), 3.86 (3H, s), 6.91 (2H, br s), 7.01 (2H, d, J=9.6 Hz), 7.55(2H, d, J=9.6 Hz).

REFERENCE EXAMPLE 273—Chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine

To a mixture of2-amino-4,5-dihydro-3-(4-methoxybenzoyl)-7H-thieno[2,3-c]thiopyrane(9.557 kg), 1,3-dicholoroacetone (4.172 kg) in tetrahydrofuran (48,79 L)was added aluminum chloride (5.424 kg) divided in 4 portions. Then, themixture was stirred under reflux for 4.5 hours and toluene (38.74 L) wasadded at 10° C. or lower, followed by dropwise addition of water (47.79L). After addition of toluene (56.83 L), the mixture was stirred and theorganic layer was separated, washed with water, saturated aqueous sodiumbicarbonate solution and then water. The solvent was distilled off untilthe content became 34.61 kg. Methanol (57.34 L) was added dropwisethereto at about 25° C. The mixture was stirred at 5° C. for 1 hour andcrystals deposited were filtered off to obtain the titled compound(11.055 kg, 88.3%). ¹H (CDCl₃) δ: 2.18 (2H, t, J=5.7 Hz), 2.68 (2H, t,J=5.7 Hz), 3.90 (5H, s), 4.94 (2H, s), 7.01 (2H, d, J=8.7 Hz), 7.16 (2H,d, J=8.7 Hz).

EXAMPLE 1

Sodium hydride (60% in oil, 360 mg) was added to a solution ofbenzimidazole (1.1 g) in DMF (40 ml) under ice cooling. After stirringat room temperature for 15 minutes, the compound obtained in ReferenceExample 15 (3.0 g) was added and then the resulting mixture was stirredat 80° C. for 3 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and then evaporated under reduced pressure toremove the solvent. The residue was subjected to column chromatographyon silica gel to obtain2-[(1H-benzimidazol-1-yl)methyl]-3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine(1.4 g, 38%) from the eluates with ethyl acetate. It was recrystallizedfrom ethyl acetate-hexane. Colorless crystals. Melting point 201-203° C.

EXAMPLE 2

A mixture of the compound obtained in Reference Example 15 (3.0 g),2,4-thiazolidinedione (1.8 g), potassium carbonate (2.1 g), and DMF (60ml) was stirred at 80° C. for 2 hours. The reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried (MgSO₄), and then evaporated under reducedpressure to remove the solvent. The residue was subjected to columnchromatography on silica gel to obtain3-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl-1,3-thiazolidine-2,4-dione(2.9 g, 80%) from the eluates with ethyl acetate-hexane (1:1). It wasrecrystallized from ethyl acetate-hexane. Colorless prisms. Meltingpoint 208-209° C.

According to the same manner, compounds of Examples 3 to 6, 8 to 17, 35,36, and 39 described in Table 4 to Table 7 were synthesized.

TABLE 4

Melting Example point Recrystallization No. Y R¹ R² (° C.) solvent 1 S

4-MeO 201-203 Ethyl acetate- hexane 2 S

4-MeO 208-209 Ethyl acetate- hexane 3 S

4-MeO 212-213 Ethyl acetate- hexane 4 S

4-MeO 260-262 Ethyl acetate- hexane 5 S

4-MeO 239-240 THF-hexane 6 S

4-MeO 234-236 Ethyl acetate- hexane 7 S

4-MeO 198-200 Ethyl acetate- hexane 8 S

4-PhCH₂O 246-248 Ethyl acetate- hexane 9 S

4-PhCH₂O 225-226 Ethyl acetate- hexane 10  O

4-MeO 268-269 Ethyl acetate- hexane

TABLE 5

Ex- am- Melting Re- ple point crystallization No. Y R¹ R² (° C.) solvent11 H₂C═C

4-MeO 187-188 Ethyl acetate- hexane 12^(a)) Me₂C═C

4-MeO Amor- phous solid 13^(b))

4-MeO Amor- phous solid 14

4-MeO 191-192 Ethyl acetate- hexane 15 Me₂C

4-MeO 212-213 Ethyl acetate- hexane 16 Me₂C

4-MeO 182-184 Ethyl acetate- hexane 17 Me₂C

4-MeO 162-164 Ethyl acetate- hexane 18 (O)S

4-MeO 233-235 THF-hexane 19 (O)S

4-MeO 252-254 Ethyl acetate- hexane 20 (O)S

4-MeO 199-201 Ethyl acetate- hexane ^(a)) ¹H NMR(200 MHz, CDCl₃) δ:1.88(2H, m), 2.22(2H, t, J=6.2Hz), 2.91(4H, s), 3.55(2H, s), 3.90(3H,s), 4.82(1H, s), 4.87(1H, s), 5.02(2H, s), 6.99(2H, d, J=8.8Hz),7.14(2H, d, J=8.8Hz). ^(b)) ¹H NMR(200 MHz, CDCl₃) δ: 1.70(2H, t,J=6.2Hz), 2.02(2H, t, J=6.2Hz), 2.91(4H, s), 3.01(2H, s), 3.90(3H, s),3.91-4.03(4H, m), 5.01(2H, s), 7.00(2H, d, J=8.8Hz), 7.16(2H, d,J=8.8Hz).

TABLE 6

Melting Example point Recrystallization No. Y R¹ R² (° C.) solvent 21(O)S

4-MeO 251-253 Ethyl acetate- hexane 22 (O)S

4-MeO 268-269 THF-hexane 23 (O)S

4-MeO 275-277 Ethyl acetate- hexane 24 (O)S

4-MeO 184-185 THF-hexane 25 (O)S

4-PhCH₂O 269-271 Ethyl acetate- hexane 26 (O)S

4-PhCH₂O 268-270 Ethyl acetate- hexane 27 (O)₂S

4-MeO >300 THF-hexane 28 (O)₂S

4-MeO 234-235 THF-hexane 29 (O)₂S

4-PhCH₂O 296-298 Ethyl acetate- hexane 30 (O)S

4-HO 274-276 Methanol-ethyl acetate-hexane

TABLE 7 Reference Melting Example point Recrystallization No. Y R¹ R² (°C.) solvent 31 (O)S

4-HO 206-209 Ethyl acetate- hexane 32 (O)₂S

4-HO >300 Ethyl acetate- hexane 33 OC

4-MeO 257-259 Ethyl acetate- hexane 34 OC

4-MeO 203-204 Ethyl acetate- hexane 35 EtOOC—CH

4-MeO 180-181 Ethyl acetate- hexane 36 PhCH₂O₂C—CH

4-MeO 149-150 Ethyl acetate- hexane 37 HOOC—CH

4-MeO 258-259 THF-hexane 38

4-MeO 170-171 Chloroform- hexane 39 PhCH₂O—CH

4-MeO 169-171 Ethyl acetate- hexane 40 HO—CH

4-MeO 218-220 Ethyl acetate- hexane

EXAMPLE 7

Sodium hydride (60% in oil, 480 mg) was added to a solution of1H-1,2,4-triazole (840 mg) in DMF (50 ml) at room temperature and theresulting mixture was stirred at room temperature for 15 minutes. Thecompound obtained in Reference Example 15 (4.0 g) was added and then theresulting mixture was stirred at 80° C. for 2 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theethyl acetate layer was washed with water, dried (MgSO₄), and thenevaporated under reduced pressure to remove the solvent. The residue wassubjected to column chromatography on silica gel to obtain3-chloro-4-(4-methoxyphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine(3.0 g, 69%) from the eluates with ethyl acetate. It was recrystallizedfrom ethyl acetate-hexane. Yellow crystals. Melting point 198-200° C.

EXAMPLE 18

To a solution of the compound obtained in Example 1 (800 mg) inmethylene chloride (20 ml) was added m-chloroperbenzoic acid (70%, 400mg) under ice cooling and then the resulting mixture was stirred at thesame temperature for 1 hour. The reaction mixture was poured into waterand extracted with methylene chloride. The methylene chloride layer waswashed with a saturated aqueous solution of sodium hydrogen carbonateand water, dried (MgSO₄), and then evaporated under reduced pressure toremove the solvent. The residue was subjected to column chromatographyon silica gel to obtain2-[(1H-benzimidazol-1-yl)methyl]-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine(530 mg, 64%) from the eluates with ethyl acetate-methanol (20:1). Itwas recrystallized from THF-hexane. Colorless prisms. Melting point233-235° C.

According to the same manner, compounds of Examples 19 to 26 describedin Table 5 and Table 6 were synthesized.

EXAMPLE 27

To a solution of the compound obtained in Example 5 (500 mg) inmethylene chloride (20 ml) was added m-chloroperbenzoic acid (70%, 609mg) under ice cooling and then the resulting mixture was stirred at roomtemperature for 1 hour. The reaction solution was poured into water andextracted with methylene chloride. The methylene chloride layer waswashed with a saturated, aqueous solution of sodium hydrogen carbonateand water, dried (MgSO₄), and then evaporated under reduced pressure toremove the solvent. The residue was subjected to column chromatographyon silica gel to obtain1-{[3-chloro-4-(4-methoxyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione(295 mg, 55%) from the eluates with ethyl acetate-hexane (1:1). It wasrecrystallized from THF-hexane. Colorless prisms. Melting point 300° C.or higher.

According to the same manner, compounds of Examples 28 to 29 describedin Table 6 were synthesized.

EXAMPLE 30

To a solution of the compound obtained in Example 25 (300 mg) inmethylene chloride (20 ml) was added a solution of titaniumtetrachloride (620 mg) in methylene chloride (10 ml) under ice coolingand then the resulting mixture was stirred at the same temperature for 8hours. The reaction mixture was poured into water and extracted withmethylene chloride. The methylene chloride layer was washed with asaturated aqueous solution of sodium hydrogen carbonate and water, dried(MgSO₄), and then evaporated under reduced pressure to remove thesolvent. The residue was subjected to column chromatography on silicagel to obtain1-{[3-chloro-4-(4-hydroxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5)thieno[2,3-b]pyridin-2-yl]methyll-2,5-pyrrolidinedione(130 mg, 52%) from the eluates with ethyl acetate-methanol (9:1). It wasrecrystallized from methanol-ethyl acetate-hexane. Colorless prisms.Melting point 274-276° C.

According to the same manner, compounds of Examples 31 and 32 describedin Table 7 were synthesized.

EXAMPLE 33

A mixture of the compound obtained in Example 13 (2.4 g), 10% aqueoushydrochloric acid (10 ml), and dioxane (25 ml) was stirred at 60° C. for2 hours and then evaporated under reduced pressure to remove thesolvent. The residue was diluted with methylene chloride and themethylene chloride solution was washed with water, dried (MgSO₄), andthen evaporated under reduced pressure to remove the solvent. Theresidue was subjected to column chromatography on silica gel to obtain1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione(1.8 g, 86%) from the eluates with chloroform-ethyl acetate (4:1). Itwas recrystallized from ethyl acetate-hexane. Colorless prisms. Meltingpoint 257-258° C.

EXAMPLE 34

According to the same manner as that described in Example 33,3-{[chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dionewas obtained except that the compound obtained in Example 14 is used. Itwas recrystallized from ethyl acetate-hexane. Colorless prisms. Meltingpoint 203-204° C.

EXAMPLE 37

To a mixture of the compound obtained in Example 36 (3.4 g), 10%palladium carbon (containing 50% water, 3.0 g), THF (30 ml), and aceticacid (60 ml) was added formic acid (6 ml) with stirring at roomtemperature and then the stirring was continued at the same temperaturefor 3 hours. After the catalyst was separated by filtration, thefiltrate was evaporated under reduced pressure. To the residue was addeddiethyl ether-methanol (10:1, 50 ml) and the resulting mixture wasstirred at room temperature for 30 minutes. The precipitated crystalswere collected by filtration and washed with diethyl ether-methanol(10:1) to obtain3-chloro-2-[(2,5-dioxopyrrolidin-1-yl)methyl]-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)[1]benzothieno[2,3-b]pyridine-7-carboxylicacid (2.6 g, 92%). It was recrystallized from THF-hexane. Colorlessprisms. Melting point 258-259° C.

EXAMPLE 38

A mixture of the compound obtained in Example 37 (500 mg), morpholine(99 mg), N,N-dimethylaminopyridine (13 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg),and DMF (10 ml) was stirred at room temperature for 10 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), and thenevaporated under reduced pressure to remove the solvent. The residue wassubjected to column chromatography on silica gel to obtain1-{[3-chloro-4-(4-methoxyphenyl)-7-[(4-morpholinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione(2.6 g, 92%) from the eluates with ethyl acetate. It was recrystallizedfrom chloroform-hexane. Colorless prisms. Melting point 170-171° C.

EXAMPLE 40

To a mixture of the compound obtained in Example 39 (1.2 g), 10%palladium carbon (containing 50% water, 1.2 g), and acetic acid (70 ml)was added formic acid (10 ml) with stirring at room temperature and thenthe stirring was continued at the same temperature for 2 hours. Afterthe catalyst was separated by filtration, the filtrate was evaporatedunder reduced pressure. To the residue was added ethyl acetate and theresulting solution was washed with a 5% aqueous ammonia solution andwater, dried (MgSO₄), and then evaporated under reduced pressure toremove the solvent. The residue was subjected to column chromatographyon silica gel to obtain1-{[3-chloro-7-hydroxy-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro[1]-benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione(1.8 g, 86%) from the eluates with ethyl acetate-hexane (2:1). It wasrecrystallized from ethyl acetate-hexane. Colorless prisms. Meltingpoint 218-220° C.

EXAMPLE 41

To a solution of the compound obtained in Example 33 (500 mg) and methyliodide (470 mg) in DMF (15 ml) was added DBU (420 mg) under ice coolingand then the resulting mixture was stirred at the same temperature for 2hours. The reaction mixture was poured into a saturated aqueous solutionof ammonium chloride (30 ml) and extracted with ethyl acetate. The ethylacetate layer was washed with water, dried (MgSO₄), and then evaporatedunder reduced pressure to remove the solvent. The residue was subjectedto column chromatography on silica gel to obtain1-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(291 mg, 55%) from the eluates with ethyl acetate-hexane (3:1). It wasrecrystallized from ethyl acetate-hexane. Colorless prisms. Meltingpoint 245-246° C.

EXAMPLE 42

According to the same manner as that described in Example 41,3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione:

was obtained except that the compound obtained in Example 34 was used.It was recrystallized from ethyl acetate-hexane. Colorless prisms.Melting point 211-212° C.

EXAMPLE 43

A mixture of the compound obtained in Reference Example 14 (512 mg),succinimide (198 mg), potassium carbonate (276 mg), and DMF (5 ml) wasstirred at 80° C. for 1 hour, then was poured into water, and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then evaporated under reduced pressure to remove thesolvent. The residue was subjected to column chromatography on silicagel to obtain1-{[7-(benzyloxy)-3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(554 mg, 96%) from the eluates with ethyl acetate-hexane (1:2). It wasrecrystallized from ethyl acetate-hexane. Colorless prisms. Meltingpoint 221-223° C.

EXAMPLE 44

To a mixture of the compound obtained in Example 43 (480 mg), 10%palladium carbon (containing 50% water, 480 mg), and THF (20 ml) wasadded formic acid (10 ml) with stirring at room temperature. After thestirring was continued at room temperature for 5 hours, the catalyst wasseparated by filtration and the filtrate was evaporated under reducedpressure. The residue was dissolved in ethyl acetate-THF (5:1) and theresulting mixture was washed with a saturated aqueous solution of sodiumhydrogen carbonate and water, dried (MgSO₄), and then evaporated underreduced pressure to remove the solvent. The residue was subjected tocolumn chromatography on silica gel to obtain1-{[3-chloro-7-hydroxy-4-(4-methoxyphenyl)-6,6-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(221 mg, 55%) as a colorless powder from the eluates with ethylacetate-hexane (1:1). Melting point 227-229° C.

EXAMPLE 45

A solution of dimethyl sulfoxide (30 mg) in methylene chloride (1 ml)was added to a solution of oxalyl chloride (37 mg) in methylene chloride(4 ml) at −78° C. under a nitrogen atmosphere. After stirring at thesame temperature for 1 hour, a solution of the compound obtained inExample 13 (70 mg) in methylene chloride (4 ml) was added thereto andthen the stirring was continued at −78° C. for 1 hour. The reactiontemperature was raised to at −30° C. and, after stirring at 30 minutes,triethylamine (150 μl) was added thereto and then the solutiontemperature was slowly raised to at 0° C. The reaction mixture waspoured into water and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and then evaporated underreduced pressure to remove the solvent. The residue was subjected tocolumn chromatography on silica gel to obtain1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(30 mg, 62%) from the eluates with ethyl acetate-hexane (1:2). It wasrecrystallized from ethanol-hexane. Colorless prisms. Melting point222-224° C.

EXAMPLE 46

A solution of 400 mg of the compound obtained in Example 22 in 350 ml of2-propanol and 100 ml of hexane was fractionated by high performanceliquid chromatography (HPLC) [column: CHIRALCEL OD 50 mmφ×500 mm(manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: 20°C., mobile phase: hexane/2-propanol=6/4, flow rate: 100 ml/minute,detection wavelength: 254 nm, and 1 shot: about 40 mg]. The fractionswere concentrated and then dissolved in 50 ml of ethanol. The resultingsolution was filtered through a 0.45-μm filter and then concentrated todryness. To the residue was added hexane and the resulting mixture wasagain concentrated to dryness to obtain a white powder.

There were obtained 153 mg (optical purity of 99.4% ee) of an enantiomerhaving a shorter retention time whose optical rotation was toward(+)-direction of the optical rotation,(R)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,and 152 mg (optical purity of 99.8% ee) of an enantiomer having a longerretention time whose optical rotation was toward (−)-direction,(S)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione.The determination of the optical purity was carried out by HPLC using achiral column (column: CHIRALPAK AD 4.6 mmφ×250 mm (manufactured byDaicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 20° C., mobilephase: hexane/ethanol=4/6, flow rate: 0.5 ml/minute, and detectionwavelength: 254 nm).

EXAMPLE 47

A solution of 1.1 g of the compound obtained in Example 22 in 500 ml ofethanol and 500 ml of 2-propanol was concentrated to make the liquidvolume about 1/2. The resulting concentrate was fractionated by highperformance liquid chromatography (HPLC) [column: CHIRALPAK AD 50mmφ×500 mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha),temperature: 20° C., mobile phase: hexane/ethanol=4/6, flow rate: 70ml/minute, detection wavelength: 254 nm, and 1 shot: about 0.8 g]. Thefractions were concentrated and then dissolved in ethanol. The resultingsolution was filtered through a 0.45-μm filter and then concentrated todryness. To the residue was added hexane and the resulting mixture wasagain concentrated to dryness to obtain a white powder.

According to the same operation, there were obtained from 3.1 g of theracemate 1.39 g (optical purity of >99.9% ee) of an enantiomer having ashorter retention time whose optical rotation was toward (+)-direction,(R)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,and 1.47 g (optical purity of 99.4% ee) of an enantiomer having a longerretention time whose optical rotation was toward (−)-direction,(S)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyll-2,5-pyrrolidinedione.

EXAMPLE 48

A solution of 980 mg of the compound obtained in Example 19 in 700 ml of2-propanol and 300 ml of ethanol was fractionated by high performanceliquid chromatography (HPLC) [column: CHIRALCEL OD 50 mmφ×500 mm(manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: 20°C., mobile phase: hexane/2-propanol=6/4, flow rate: 100 ml/minute,detection wavelength: 254 nm, and 1 shot: about 40 mg]. The fractionswere concentrated and then dissolved in ethanol. The resulting solutionwas filtered through a 0.45-μm filter and then concentrated to dryness.To the residue was added hexane and the resulting mixture was againconcentrated to dryness to obtain a white powder.

There were obtained 188 mg (optical purity of 99.4% ee) of an enantiomerhaving a shorter retention time whose optical rotation was toward(+)-direction,(R)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione,and 153 mg (optical purity of 99.0% ee) of an enantiomer having a longerretention time whose optical rotation was toward (−)-direction,(S)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione.

EXAMPLE 49

A solution of 1.0 g of the compound obtained in Example 19 in 900 ml ofethanol and 100 ml of acetonitrile was concentrated to make the liquidvolume about 1/2. The resulting concentrate was fractionated by HPLC[column: CHIRALPAK AD 50 mmφ×500 mm (manufactured by Daicel Kagaku KogyoKabushiki Kaisha), temperature: 20° C., mobile phase:hexane/ethanol=4/6, flow rate: 100 ml/minute, detection wavelength: 254nm, and 1 shot: about 1.2 g]. The fractions were concentrated and thendissolved in ethanol. The resulting solution was filtered through a0.45-μm filter and then concentrated to dryness. To the residue wasadded hexane and the resulting mixture was again concentrated to drynessto obtain a white powder.

According to the same operation, there were obtained from 2.5 g of theracemate 1.21 g (optical purity of >99.9% ee) of an enantiomer having ashorter retention time whose optical rotation was toward (+)-direction,(R)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione,and 1.14 g (optical purity of 99.8% ee) of an enantiomer having a longerretention time whose optical rotation was toward (−)-direction,(S)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione.

EXAMPLE 50

A mixture of 10 mg of the compound obtained in Example 47,(R)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,90 mg of lactose, and 70 mg of microcrystalline cellulose was granulatedwith a solution of 1.4 mg of hydroxypropyl cellulose in 70 μl of water.The granules were encapsulated into a gelatin capsule.

EXAMPLE 51

A mixture of 10 mg of the compound obtained in Example 47,(S)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,90 mg of lactose, and 70 mg of microcrystalline cellulose was granulatedwith a solution of 1.4 mg of hydroxypropyl cellulose in 70 μl of water.The granules were encapsulated into a gelatin capsule.

EXAMPLE 52

A mixture of 10 mg of the compound obtained in Example 49,(R)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione,90 mg of lactose, and 70 mg of microcrystalline cellulose was granulatedwith a solution of 1.4 mg of hydroxypropyl cellulose in 70 μl of water.The granules were encapsulated into a gelatin capsule.

EXAMPLE 53

A mixture of 10 mg of the compound obtained in Example 49,(S)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione,90 mg of lactose, and 70 mg of microcrystalline cellulose was granulatedwith a solution of 1.4 mg of hydroxypropyl cellulose in 70 μl of water.The granules were encapsulated into a gelatin capsule.

EXAMPLE 54

A mixture of 10 mg of the compound obtained in Example 47,(R)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,35 mg of lactose, 150 mg of corn starch, and 20 mg of microcrystallinecellulose was granulated with a solution of 1.4 mg of hydroxypropylcellulose in 70 μl of water. To the granules were added 10 mg ofmicrocrystalline cellulose and 2.5 mg of magnesium stearate, followed bymixing. The resulting mixture was subjected to compression molding toprepare a tablet.

EXAMPLE 55

A mixture of 10 mg of the compound obtained in Example 47,(S)-1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione,35 mg of lactose, 150 mg of corn starch, and 20 mg of microcrystallinecellulose was granulated with a solution of 1.4 mg of hydroxypropylcellulose in 70 μl of water. To the granules were added 10 mg ofmicrocrystalline cellulose and 2.5 mg of magnesium stearate, followed bymixing. The resulting mixture was subjected to compression molding toprepare a tablet.

EXAMPLE 56

A mixture of 10 mg of the compound obtained in Example 49,(R)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione,35 mg of lactose, 150 mg of corn starch, and 20 mg of microcrystallinecellulose was granulated with a solution of 1.4 mg of hydroxypropylcellulose in 70 μl of water. To the granules were added 10 mg ofmicrocrystalline cellulose and 2.5 mg of magnesium stearate, followed bymixing. The resulting mixture was subjected to compression molding toprepare a tablet.

EXAMPLE 57

A mixture of 10 mg of the compound obtained in Example 49,(S)-3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazoldine-2,4-dione,35 mg of lactose, 150 mg of corn starch, and 20 mg of microcrystallinecellulose was granulated with a solution of 1.4 mg of hydroxypropylcellulose in 70 μl of water. To the granules were added 10 mg ofmicrocrystalline cellulose and 2.5 mg of magnesium stearate, followed bymixing. The resulting mixture was subjected to compression molding toprepare a tablet.

EXAMPLE 58

To a mixture of the compound obtained in Example 23 (4.5 g), ethanol(100 ml), and THF (100 ml) was added hydrazine hydrate (20 ml) at roomtemperature. This mixture was stirred at 70° C. for 2 hours and thenevaporated under reduced pressure. The residue was diluted withchloroform and the resulting solution was washed with water, dried(MgSO₄), and then evaporated under reduced pressure to remove thesolvent to obtain2-aminomethyl-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine:

(3.0 g, 89%). It was recrystallized from ethyl acetate-hexane. Colorlessprisms. Melting point 300° C. or higher.

EXAMPLE 59

To a mixture of the compound obtained in Example 33 (1.5 g),N-fluorobis(benzenesulfon)imide (2.6 g), and DMF (45 ml) was added DBU(2.0 g) under ice cooling and then the resulting mixture was stirred for3 hours. The reaction mixture was poured into a saturated aqueoussolution of ammonium chloride (150 ml) and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), and thenevaporated under reduced pressure to remove the solvent. The residue wassubjected to column chromatography on silica gel and to obtain1-{[3-chloro-8-fluoro-7-hydroxy-4-(4-methoxyphenyl)-[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(750 mg, 48%) from the eluates with chloroform-hexane-ethyl acetate(2:2:1). It was recrystallized from THF-hexane. Colorless prisms.Melting point 294-295° C.

EXAMPLE 60

To a solution of the compound obtained in Example 59 (250 mg) in DMF (5ml) was added sodium hydride (60% in oil, 25 mg) under ice cooling.After stirring at room temperature for 10 minutes, iodomethane (150 mg)was added thereto and then the stirring was continued for 30 minutes.The reaction mixture was poured into water and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and then evaporated under reduced pressure to remove the solvent toobtain1-{[3-chloro-8-fluoro-7-methoxy-4-(4-methoxyphenyl)[1]-benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione(190 mg, 74%). It was recrystallized from THF-hexane. Colorless prisms.Melting point 215-216° C.

EXAMPLE 61

To a mixture of the compound obtained in Example 45 (200 mg),iodomethane (176 mg), and DMF (6 ml) was added DBU (158 mg) under icecooling. The reaction solution was stirred at 0° C. for 20 minutes, thenpoured into a saturated aqueous solution of ammonium chloride, andextracted with ethyl acetate-THF (5:1). The extract was washed withwater, dried (MgSO₄), and then evaporated under reduced pressure toremove the solvent. The residue was subjected to column chromatographyon silica gel to obtain1-{[3-chloro-4-(4-methoxyphenyl)-6,6,8,8-tetramethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(140 mg, 66%) from the eluates with ethyl acetate-hexane. A colorlesspowder. Melting point 214-216° C.

EXAMPLE 62

To a mixture of the compound obtained in Example 45 (220 mg),N-fluorobis(benzenesulfon)imide (391 mg), and DMF (6 ml) was added DBU(158 mg) under ice cooling. The reaction mixture was stirred at 0° C.for 30 minutes and then poured into a saturated aqueous solution ofammonium chloride and extracted with ethyl acetate-THF (5:1). Theextract was washed with water, dried (MgSO₄), and then evaporated underreduced pressure to remove the solvent. The residue was subjected tocolumn chromatography on silica gel to obtain1-{[3-chloro-8,8-difluoro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(85 mg) from the eluates with ethyl acetate-hexane-methanol (1:2:0.1).It was recrystallized from ethanol-isopropyl ether. Colorless prisms.Melting point of 200-202° C.

EXAMPLE 63

A mixture of the compound obtained in Example 33 (2.0 g), hydroxylaminehydrochloride (673 mg), water (5 ml), methanol (5 ml), and THF (40 ml)was heat under reflux for 2 hours and then evaporated under reducedpressure to remove the solvent. The residue was dissolved in methylenechloride and the resulting solution was washed with a saturated, aqueoussolution of sodium hydrogen carbonate and water, dried (MgSO₄), and thenevaporated under reduced pressure to remove the solvent. The residue wassubjected to column chromatography on silica gel to obtain(Z)-1-{[3-chloro-7-(hydroxyimino)-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:

(810 mg, 39%) from the eluates with ethyl acetate-chloroform (1:1) as aless polar portion. It was recrystallized from THF-hexane. Colorlessprisms. Melting point 248-249° C.

In addition,(E)-1-{[3-chloro-7-(hydroxyimino)-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedone:

(226 mg, 11%) was obtained from a more polar portion. It wasrecrystallized from THF-hexane. Colorless prisms. Melting point 250-251°C.

EXAMPLE 64

To a mixture of the compound obtained in Example 32 (150 mg),triethylamine (41 mg), methylene chloride (4 ml) and DMF (0.4 ml) wasadded acetyl chloride (27 mg) under ice-cooling. The reaction mixturewas stirred at room temperature for 30 minutes, poured into water andthen extracted with ethyl acetate. The ethyl acetate layer was washedwith water, and dried (MgSO₄). The solvent was distilled off underreduce pressure to obtain4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenylacetate(75 mg, 46%). It was recrystallized from acetone-hexane. Colorlessprisms. Melting point 272-273° C.

According to the same manner, compounds of Examples 65 to 72 shown inTable 8 were synthesized.

TABLE 8

Melting Example point Recrystallization No. R (° C.) solvent 64 COMe272-273 acetone-hexane 65 COEt 268-269 acetone-hexane 66 CO^(t)Bu305-306 ethyl acetate- hexane 67 CO(CH₂)₁₄Me 160-161 acetone-hexane 68COCH₂OMe 207-208 ethyl acetate- hexane 69 COCH₂Cl 167-168 acetone 70

281-282 THF-hexane 71

178-179 ethyl acetate- hexane 72

156-157 acetone-hexane 73 COCH₂NMe₂.HCl 199-200 ethanol-hexane 74P(O)Me₂ 253-254 THF-hexane 75 P(O)(cyc.Hex)₂ 167-168 ethyl acetate-hexane 76 P(O)(OEt)₂ 204-205 ethyl acetate- hexane 77 P(O)(OPh)₂ 200-201THF-hexane 78 P(O)(OCH₂CH₂CH₂Me)₂ amor- IR(KBr): 1775, phous 1713, 1329,1279 solids cm⁻¹ 79 P(O)(OCH₂CHMe₂)₂ amor- IR(KBr): 1775, phous 1713,1331, 1275 solids cm⁻¹ 80 P(O)(OCH₂CH₂CH₂CH₂Me)₂ amor- IR(KBr): 1775,phous 1711, 1324, 1277 solids cm⁻¹ 81 CONHCH₂CH₂Me 164-165 THF-hexane 82CONHCH₂CH₂CH₂Me 150-152 ethyl acetate- hexane 83 CONH(cyc.Hex) 260-261THF-hexane 84 CONHCH₂COOEt 202-203 ethyl acetate- hexane 85 SO₂CHMe₂288-289 THF-hexane 86 SO₂CH₂CHMe₂ 215-216 acetone-hexane 87

327-328 DMSO-water 88 CONMe₂ 290-291 chloroform- hexane

EXAMPLE 73

A mixture of the compound obtained in Example 32 (462 mg),dimethylglycine (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC, 556 mg) and pyridine (8 ml) was stirred at roomtemperature for 10 hours and then the solvent was removed under reducedpressure. The residue was diluted with ethyl acetate (10 ml) and themixture was washed with water and dried (MgSO₄) The solvent was removedunder reduced pressure and the residue (210 mg) was dissolved inchloroform (2 ml). To the solution was added 4 N hydrochloric acid-ethylacetate solution (0.09 ml) with stirring under ice-cooling and themixture was further stirred for 10 minutes. The reaction mixture wasconcentrated under reduced pressure to obtain crystals of4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)-methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]-thieno[2,3-b]pyridin-4-yl}phenyl(dimethylamino)acetate hydrochloride. It was recrystallized fromethanol-hexane. Colorless crystals. Melting point 199-200° C.

EXAMPLE 74

To a mixture of the compound obtained in Example 32 (100 mg),triethylamine (70 mg) and methylene chloride (3 ml) was addeddimethylphosphinic chloride (97%, 73 mg) under ice-cooling. The reactionmixture was stirred at room temperature for 2 hours, poured into water,and extracted with ethyl acetate. The ethyl acetate layer was washedwith water and dried (MgSO₄) and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography to obtain4-{3-chloro-2-{(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dhydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyldimethylphosphinate(67 mg, 58%) from the fraction eluted with ethyl acetate-methanol(10:1). It was recrystallized from THF-hexane. Colorless prisms. Meltingpoint 253-254° C.

According to the same manner, the compound of Example 75 shown in Table8 was synthesized.

EXAMPLE 76

To a mixture of the compound obtained in Example 32 (300 mg), THF (6 ml)and DMF (0.5 ml) was added sodium hydride (60% in oil, 37 mg) underice-cooling and then the mixture was stirred for 15 minutes.Diethylphosphoryl chloride (217 mg) was added thereto and the stirringwas continued for additional 3 hours under ice-cooling. The reactionmixture was poured into water and extracted with ethyl acetate. Theethyl acetate layer was washed with water and dried (MgSO₄) and thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography to obtain4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyldiethylphosphate(200 mg, 52%) from the fraction eluted with ethyl acetate-hexane (4:1).It was recrystallized from ethyl acetate-hexane. Colorless prisms.Melting point 204-205° C.

According to the same manner, the compounds of Examples 77 to 80 shownin Table 8 were synthesized.

EXAMPLE 81

To a mixture of the compound obtained in Example 32 (300 mg),triethylamine (127 mg) and methylene chloride (6 ml) was addedpropylisocyanate (80 mg) under ice-cooling. The reaction mixture wasstirred at room temperature for 10 hours, poured into water, and thenextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄) and the solvent was distilled off under reducedpressure. The residue was subjected to silica gel column chromatographyto obtain4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyl-propylcarbamate(220 mg. 62%) from the fraction eluted with ethyl acetate-hexane (2:1).It was recrystallized from THF-hexane. Colorless prisms. Melting point164-165° C.

According to the same manner, the compounds of Examples 82 to 84 shownin Table 8 were synthesized.

EXAMPLE 85

To a mixture of the compound obtained in Example 32 (250 mg),triethylamine (106 mg) and methylene chloride (5 ml) was addedisopropylsulfonyl chloride (112 mg) under ice-cooling. The reactionmixture was stirred at room temperature for 3 hours, poured into waterand extracted with ethyl acetate. The ethyl acetate layer was washedwith water and dried (MgSO₄) and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography to4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyl2-propane sulfonate (200 mg, 66%) from the fraction eluted with ethylacetate-hexane (2:1). It was recrystallized from THF-hexane. Colorlessprisms. Melting point 288-289° C.

According to the same manner, the compound of Example 86 shown in Table8 was synthesized.

EXAMPLE 87

To a solution of the compound obtained in Example 32 (300 mg) inpyridine (5 ml) was added 4-morphonylcarbonyl chloride (188 mg) at roomtemperature. The reaction mixture was stirred to 10 hours and thencrystals of4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenylmorpholine carboxylate deposited was filtered off and washed with water.It was recrystallized from DNSO-water (152 mg, 41%). Pale yellow prisms.Melting point 327-328° C.

EXAMPLE 88

To a solution of the compound obtained in Example 32 (200 mg) inpyridine (4 ml) was added dimethylcarbamoyl chloride (113 mg) at roomtemperature. The reaction mixture was stirred for 10 hours, poured intowater and extracted with ethyl acetate. The ethyl acetate layer waswashed with water and dried (MgSO₄) and the solvent was distilled offunder reduced pressure. The residue was subjected to silica gel columnchromatography to obtain4-{3-chloro-2-[2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenyldimethylcarbamate (180 mg, 79%) from the fraction eluted with ethylacetate-hexane (2:1). It was recrystallized from chloroform-hexane.Colorless prisms. Melting point 290-291° C.

EXAMPLE 89

To a mixture of the compound obtained in Example 32 (500 mg),triethylamine (138 mg) and methylene chloride (10 ml) was added methylchlorocarbonate (109 mg) under ice-cooling. The reaction mixture wasstirred at room temperature for 1 hour, poured into water and thenextracted with ethyl acetate. The ethyl acetate layer was washed withwater and dried (MgSO₄) and the solvent was distilled off under reducedpressure to obtain4-{3-chloro-2-[2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenylmethylcarbonate (480 mg, 86%). It was recrystallized from ethylacetate-hexane. Colorless prisms. Melting point 275-276° C.

According to the same manner, compounds of Examples 90 to 101, 103, 104,107 and 108 shown in Table 9 were synthesized.

TABLE 9

Melting Example point Recrystallization No. R¹ R^(2a)) (° C.) solvent 89 COOMe suc 275-276 ethyl acetate- hexane  90 COOEt suc 231-232 ethylacetate- hexane  91 COOCH₂CH₂Me suc 156-157 ethyl acetate- hexane  92COO(CH₂)₃Me suc 173-174 acetone-hexane  93 COOCHMe₂ suc 239-240 ethylacetate- hexane  94 COOCH₂CHMe₂ suc 237-238 ethyl acetate- hexane  95COO(CH₂)₄Me suc 143-144 THF-hexane  96 COO(CH₂)₅Me suc amorphousIR(KBr): 1765, solids 1707 cm⁻¹  97 COO(CH₂)₇Me suc amorphous IR(KBr):1759, solids 1709 cm⁻¹  98 COOCH₂Ph suc 160-161 ethyl acetate- hexane 99 COO(CH₂)₂OMe suc 137-138 THF-hexane 100 COOCH₂CH═CH₂ suc 209-210THF-hexane 101 COOCH₂CMe₃ suc 284-285 THF-hexane 102 H thia 219-220acetonitrile- hexane 103 COO(CH₂)₃Me thia 163-164 ethyl acetate- hexane104 COOCH₂CHMe₂ thia 155-156 ethyl acetate- hexane 105 Me pht 298-299THF-hexane 106 H pht 342-343 methyl ethyl ketone-hexane 107 COO(CH₂)₃Mepht 172-173 ethyl acetate- hexane 108 COOCH₂CHMe₂ pht 175-176 ethylacetate- hexane

TABLE 10

Melting Example point Recrystallization No. R m (° C.) solvent 109CH₂OCH₂Ph 2 122-123 ethyl acetate- hexane 110 CH₂COOEt 2 215-216 ethylacetate- hexane 111 H 0 302-303 ethyl acetate- hexane 112 CH₂COO^(t)Bu 0191-192 ethyl acetate- hexane 113 CH₂COO^(t)Bu 1 175-176 ethyl acetate-hexane 114 CH₂COO^(t)Bu 2 204-205 ethyl acetate- hexane 115 CH₂COOH 1205-206 methanol-diethyl ether 116 CH₂COOH 2 260-261 acetone-hexane 117CH₂CONHCH₂Ph 1 220-221 THF-hexane

EXAMPLE 102

A mixture of the compound obtained in Example 28 (2.2 g), DL-methionine(1.9 g) and methanesulfonic acid (20 ml) was stirred at 100° C. for 2hours. The reaction mixture was ice-cooled and 15% aqueous ammoniasolution (100 ml) was slowly added thereto under ice-cooling. Afterstirring for additional 30 minutes,3-{[3-chloro-4-(4-xyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano-4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}thiazolidine-2,4-dionedeposited was filtered off and washed with water. After drying, it wasrecrystallized from acetonitrile-dietyl ether (920 mg, 44%). Colorlessprisms. Melting point 219-220° C.

According to the same manner, the compounds of Example 106 and Example111 shown in Table 9 and Table 10 were synthesized.

EXAMPLE 105

To a solution of the compound obtained in Example 6 (2.8 g) in methylenechloride (60 ml) was added m-chloroperbenzoic acid (70%, 3.0 g) underice-cooling and the mixture was stirred at room temperature for 1 hour.The reaction mixture was washed with an aqueous saturated sodiumbicarbonate solution and then water, and dried (MgSO4) and the solventwas distilled off under reduced pressure to obtain crystals of2-}[3-chloro-4-(4-methoxyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (2.0 g, 69%). It was recrystallized from THF-hexane.Colorless prisms. Melting point 298-299° C.

EXAMPLE 109

To a solution of the compound obtained in Example 32 (100 mg) in DMF (3ml) was added sodium hydride (60% in oil, 11 mg) under ice-cooling andthe mixture was stirred for 10 minutes. After addition of benzylchloromethyl ether (65 mg) thereto, the mixture was stirred at 70° C.for 1 hour. The reaction mixture was poured into water and extractedwith ethyl acetate. The ethyl acetate layer was washed with water anddried (MgSO₄) and the solvent was distilled off under reduced pressure.The residue was subjected to silica gel column chromatography to obtain1-[(4-{4-[benzyloxy)methoxy]phenyl}-3-chloro-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl)methyl]-2,5-pyrrolidinedionefrom the fraction eluted with ethyl acetate-hexane (3:2). It wasrecrystallized from ethyl acetate-hexane (35 mg, 28%). Colorless prisms.Melting point 122-123° C.

EXAMPLE 110

To a solution of the compound obtained in Example 32 (100 mg) in DMF (3ml) was added sodium hydride (60% in oil, 11 mg) under ice-cooling andthe mixture was stirred for 15 minutes. After addition of ethylbromoacetate (70 mg) thereto, the mixture was further stirred at roomtemperature for 30 minutes. The reaction mixture was poured into waterand extracted with ethyl acetate. The ethyl acetate layer was washedwith water and dried (MgSO₄) and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography to obtain ethyl(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxidO-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetatefrom the fraction eluted with ethyl acetate-hexane (3:2). It wasrecrystallized from ethyl acetate-hexane (30 mg, 25%). Colorless prisms.Melting point 215-216° C.

EXAMPLE 112

To a solution of the compound obtained in Example 111 (5.0 g) in DMF (50ml) was added sodium hydride (60% in oil, 539 mg) under ice-cooling andthe mixture was stirred for 15 minutes. After addition of tert-butylbromoacetate (70 mg) thereto, the mixture was further stirred for 1.5hours. The reaction mixture was poured into water and extracted withethyl acetate. The ethyl acetate layer was washed with water and dried(MgSO₄) and the solvent was distilled off under reduced pressure. Theresidue was subjected to silica gel column chromatography to obtaintert-butyl(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]-thieno[2,3-b]pyridin-4-yl}phenoxy)acetatefrom the fraction eluted with ethyl acetate-hexane-chloroform (1:5:5).It was recrystallized from ethyl acetate-hexane (3.3 g, 53%). Colorlessprisms. Melting point 191-192° C.

EXAMPLE 113

To a solution of the compound obtained in Example 112 (2.7 g) inmethylene chloride (50 ml) was added m-chloroperbenzoic acid (70%, 1.2g) under ice-cooling and the mixture was stirred at room temperature for1 hour. The reaction mixture was washed with an aqueous saturated sodiumbicarbonate solution and then water and dried (MgSO₄) and the solventwas distilled off under reduced pressure. The residue was subjected tosilica gel column chromatography to obtain tert-butyl(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno(2,3-b]pyridin-4-yl}phenoxy)-acetatefrom the fraction eluted with ethyl acetate. It was recrystallized fromethyl acetate-hexane (2.2 g, 79%). Colorless prisms. Melting point175-176° C.

EXAMPLE 114

To a solution of the compound obtained in Example 112 (300 mg) inmethylene chloride (6 ml) was added m-chloroperbenzoic acid (70%, 278mg) under ice-cooling and the mixture was stirred at room temperaturefor 1 hour. The reaction mixture was washed with an aqueous saturatedsodium bicarbonate solution and then water and dried (MgSO₄) and thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography to obtain tert-butyl(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetatefrom the fraction eluted with ethyl acetate-hexane (3:2). It wasrecrystallized from ethyl acetate-hexane (235 mg, 74%). Colorlessprisms. Melting point 204-205° C.

EXAMPLE 115

A solution of the compound obtained in Example 113 (600 mg) in formicacid (7 ml) was stirred at room temperature for 6 hours and thenconcentrated under reduced pressure. The residue was diluted withmethylene chloride and washed with water and dried (MgSO₄) and thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography to obtain(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)aceticacid from the fraction eluted with chloroform-ethyl acetate (7:1) andthen chloroform-methanol (10:1) (476 mg, 88%). It was recrystallizedfrom methanol-hexane. Colorless prisms. Melting point 205-206° C.

EXAMPLE 116

A mixture of the compound obtained in Example 114 (200 mg), 10% aqueoushydrochloric acid (3 ml) and dioxane (5 ml) was stirred at 80° C. for 30minutes. The reaction mixture was cooled to room temperature and pouredinto water. The mixture was extracted with ethyl acetate. The ethylacetate layer was washed with water and dried (MgSO₄) and the solventwas distilled off under reduced pressure to obtain(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]-thieno[2,3-b]pyridin-4-yl}phenoxy)aceticacid (130 mg, 72%). It was recrystallized from acetone-hexane. Colorlessprisms. Melting point 260-261° C.

EXAMPLE 117

A mixture of the compound obtained in Example 115 (104 mg), benzylamine(24 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC, 42 mg), 1-hydroxy-1H-benzimidazole monohydrate (HOBt, 34 mg) andDMF (3 ml) was stirred at room temperature for 10 hours. The reactionmixture was poured into water. The mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and dried (MgSO₄)and the solvent was distilled off under reduced pressure. The residuewas subjected to silica gel column chromatography to obtainN-benzyl-2-(4-}3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetamidefrom the fraction eluted with ethyl acetate-methanol (6:1) (70 mg, 57%).It was recrystallized from THF-hexane. Colorless prisms. Melting point220-221° C.

EXAMPLE 1182-{[3-Chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione

To a mixture of phthalimide potassium (6.2 kg) and dimethylformamide(110.74 L) was added3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine(11.055 kg) obtained in Reference Example 27 and the mixture was stirredat 60 to 65° C. for 1 hour. After cooling to 25° C., water (36.91 L) wasadded dropwise thereto and the mixture was stirred at the sametemperature for 1 hour. The crystals deposited was filtered off andwashed with water (29. 14 L) to obtain the titled compound (14.057 kg,99.4%). ¹H-NMR (CDCl₃) δ: 2.14 (2H, t, J=5.7 Hz), 2.64 (2H, t, J=5.7Hz), 3.80 (2H, s), 3.89 (3H, s), 5.20 (2H, s), 6.98-7.13 (2H, s),6.98-7.13 (3H, m), 7.75-7.78 (2H. m), 7.79-7.794 (2H, m).

EXAMPLE 1192-{[3-Chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione

To N-methylpyrrolidone (140.56 L) was added2-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione(14.056 kg) and the mixture was dissolved by heating at about 40° C.Then, vanadium (IV) oxyacetylacetone (49.09 g) was added thereto and the30% hydrogen peroxide was added dropwise, while maintaining at 20 to 23°C. The mixture was stirred at the same temperature for 1 hour and thencooled to 3° C., followed by adding dropwise 0.5 N sodium thiosulfate (5L) and then water (281.14 L). The mixture was stirred for 1 hour underice-cooling. The crystals deposited was filtered off, dried anddissolved in N-methylpyrrolidone (135.65 L). Active carbon (678 g) wasadded and the mixture was stirred at room temperature for 30 minutes.The active carbon was filtered off and washed with N-methylpyrrolidone(13.565 L). The filtrate and washings were combined and to the mixturewas added dropwise isopropyl ether (298.43 L). The crystals depositedwere filtered off, washed with isopropyl ether (67.83 L ×2) to obtainthe titled compound (9.56 kg, 64.3%). ¹H-NMR (CDCl₃) δ: 2.01-2.19 (1H,m), 2.54-2.73 (2H, m), 3.00-3.07 (1H, m), 3.89 (3H, s), 3.95 (1H, d,J=16.9 Hz), 4.05 (1H, d, J=16.9 Hz), 5.20 (2H, s), 6.99-7.03 (2H, m),7.16-7.20 (2H, m), 7.76-7.80 (2H, m), 7.91-7.95 (2H, m).

EXAMPLE 1202-(Amonomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine

To a mixture of2-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione(8.94 kg) and diethylene glycol dimethyl ether (44.7 L) was addeddropwise hydrazine hydrate (100%, 8.56 kg) and stirred at 60° C. for 5.5hours. Water (44.7 L) was added dropwise and the mixture was cooled toroom temperature. Isopropyl ether (32.4 kg) was added and the mixturewas stirred for 1 hours. The deposited crystals were filtered off andwashed with water (17.88 L) and isopropyl ether (8.94 kg) to obtain thetitled compound (9.56 kg, 64.3%). ¹H-NMR (CDCl₃)5: 2.13-2.19 (1H, m),2.54-2.73 (2H, m), 3.00-3.09 (1H, m), 3.89 (3H, s), 4.05 (1H, d, J=16.9Hz), 4.09 (1H, d, J=16.9 Hz), 4.20 (2H, s), 6.98-7.03 (2H, m), 7.16-7.19(2H, m).

EXAMPLE 121(S)-2-(Aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine

To methanol heated to 60° C. (63 L) was added2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine(6.5 kg) and the mixture was stirred for 5 minutes, followed by additionof (R)-(−)-hydrogenphosphate-1,1′-bihaphthyl-2,2′-diyl (3.455 kg). Themixture was stirred at 60° C. for 10 minutes, slowly cooled to 25° C.After stirring for 1 hours, crystals were filtered off and washed withmethanol (13L). Methanol-ethanol (1:3, 63 L) was heated to 75° C. andthe resultant crystals were added thereto. The mixture was slowly cooledto 25° C. and stirred for 1 hours. Crystals deposited were filtered offand washed with methanol-ethanol (1:1, 13 L). The crystals weredissolved in tetrahydrofuran-water (3:1, 121. 4 L) and active carbon(242 g) was added thereto. The mixture was stirred at room temperaturefor 15 minutes and the active carbon was filtered off. Thetetrahydrofuran layer was distilled off under reduced pressure and theresultant aqueous layer was stirred at 25° C. to deposit crystals. Thecrystals were filtered off to obtain a diastereomer salt of(S)-2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridinewith (R)-(−)-hydrogenphosphate-1,1′-binaphthyl-2,2′-diyl (4.618 kg,37.7%). ¹H-NMR (DMSO-d₆) δ: 1.98-2.04 (1H, m), 2.35-2.43 (1H, m),2.71-2.81 (1H, m), 3.01-3.06 (1H, m), 3.83 (3H, s), 3.18 (1H, d, J=17.1Hz), 4.26 (1H, d, J=17.1 Hz), 4.35 (2H, s), 0.07-7.43 (12H, m),7.96-8.10 (4H, m), 8.64 (3H, bs).

This diastereomer salt (1.538 kg) was added to a mixture of dimethylsulfoxide (8.1 L), water (7.8 L), dichloromethane (16.2 L) and a 25%aqueous ammonium solution (324 ml) and the mixture was stirred. Afterdissolution of crystals, the dichloromethane layer was separated. Theaqueous layer was further extracted with dichloromethane. The extractswere combined and washed with 1% saline (16. 2 L×2) and concentrated sothat the weight of the content became 2.98 kg. To the residue was addeddropwise isopropyl ether (3.26 L) with stirring and the mixture wasallowed to stand overnight. The resultant crystals were filtered off toobtain the titled compound. ¹H-NMR (CDCl₃) δ: 2.14-2.22 (1H, m),2.60-2.77 (2H, m), 3.07-3.13 (1H, m), 3.91 (3H, s), 4.06 (1H, d, J=15Hz), 4.14 (1H, d, J=15 Hz), 4.23 (2H, s), 7.01-7.06 (2H, m), 7.17-7.21(2H, m).

EXAMPLE 1221-{[3-Chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione

To dimethyl sulfoxide (2450 ml) was added 28% sodium methoxide (97.4 g),followed by addition of succinimide (178.9 g). The mixture was stirredat about 20° C. for 30 minutes and then3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano[4′,3′:4,5]thieno-[2,3-b]pyridine(490 g) was added thereto. The mixture was stirred at room temperaturefor 2.5 hours and then a mixture of methanol (1225 ml) and water (490 g)was added dropwise thereto. The mixture was stirred at 10° C. or lowerand crystals deposited were filtered off to the titled compound (546 g,96. 3%).

EXAMPLE 1231-{[3-Chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione

A mixture of1-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione(239.6 g) and dimethylformamide (1.8 L) was cooled to −7° C. andvanadium (IV) oxyacetylacetone (691 mg) was added thereto. 30% Hydrogenperoxide (59.2 g) was added dropwise and the mixture was stirred at 2°C. or lower for 8 hours. 0.5N Sodium thiosulfate (100 ml) and water (3L) were added dropwise at 5 to 7° C. and the mixture was stirred at 15to 20° C. for 1 hour. Crystals deposited were filtered off to obtain thetitled compound (242 g, 97.5%). ¹H-NMR (CDCl₃) δ: 2.13-2.20 (1H, m),2.54-2.73 (2H, m), 3.02-3.09 (1H, m), 3.90 (3H, s), 4.00 (1H, d, J=16.9Hz), 4.10 (1H, d, J=16.9 Hz), 5.00 (1H, d, J=17.2 Hz), 5.06 (1H, d,J=17.2 Hz), 7.01 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz).

EXAMPLE 124(S)-1-{[-3-Chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione

To a solution of succinic anhydride (303.25 g) in DMF (3.5.L) was added(S)-2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine(1134 g) and the mixture was stirred for 1 hour. To the mixture wasslowly added carbonyldiimidazole (935.5 g), and stirred at roomtemperature for 22 hours and further at 36 to 38° C. for 5 hours. Thereaction mixture was added dropwise to water (20 L). After stirring for2.5 hours, crystals deposited were filtered off and washed with water(1277 g, 86.4%). This product was dissolved in a mixture of acetonitrile(8.7 L) and water (2.9 L) and treated with active carbon. Water (45 L)was added and crystals were filtered off. The crystals were suspended inacetone (2.9 L), stirred at 48 to 52° C. for 1 hour and cooled to roomtemperature. Crystals were filtered off to obtain the titled compound(997 g). Melting point 217-218.5° C. (decomp.) [α]_(D) ²⁰−123.63(c=0.00490, CHCl₃).

Elemental analysis for C₂₂H₁₉ClN₂O₄S₂; Calcd: C, 55.63; H, 4.03; N,5.90; Found: C, 55.58; H, 4.18; N, 5.94; ¹H-NMR (CDCl₃) δ: 2.13-2.20(1H, m), 2.54-2.73 (2H, m), 2.91 (4H, s), 3.02-3.09 (1H, m), 3.90 (3H,s), 4.00 (1H, d, J=16.9 Hz), 4.10 (1H, d, J=16.9 Hz), 5.00 (1H, d,J=17.2 Hz), 5.06 (1H, d, J=17.2 Hz), 7.01 (2H, d, J=8.1 Hz), 7.16 (2H,d, J=8.1 Hz).

As described hereinabove, since compounds (I) or salts thereof of thepresent invention have excellent anti-inflammatory activity, they areuseful as anti-inflammatory drugs, particularly as remedies forarthritis. Further, they are useful in the prevention and treatment ofbone destruction, osteoporosis, and the like, which accompany arthritis,because they have excellent suppressing effects on bone resorption.Furthermore, they are useful in the prevention and treatment of diseasesassociated with immune reactions including autoimmune disease becausethey have excellent suppressing effects on immune cytokine production.They are also useful as prophylactic and therapeutic drugs of rejectionreaction after organ transplantation. Moreover, compounds (I) or saltsthereof of the present invention are low in toxicity and stable againstthe metabolism in the living body so that they exert the medicalefficacy for a long period of time and can be advantageously used asmedicaments.

What is claimed is:
 1. A compound selected from the group consisting of:3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dioneor an optically active compound thereof or a salt thereof;3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dioneor an optically active compound thereof or a salt thereof;1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedioneor an optically active compound thereof or a salt thereof; and1-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-b]pyridin-7,2′-[1,3]dioxolan]-2-yl]methyl}-2,5-pyrrolidinedioneor a salt thereof.